Hexahydrocyclopentyl[f]indazole sulfonamides and derivatives thereof as selective glucocorticoid receptor modulators

ABSTRACT

The present invention is directed to hexahydrocyclopentylf]indazole carboxamides and derivatives thereof as selective glucocorticoid receptor ligands useful for treating a variety of autoimmune and inflammatory diseases or conditions. Pharmaceutical compositions and methods of use are also included.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a U.S. National Phase application under 35 U.S.C.§371 of PCT Application No. PCT/US2009/034968, filed Feb. 24, 2009,which claims priority under 35 U.S.C. §119(e) from U.S. ProvisionalApplication Ser. Nos. 61/068,370, filed Mar. 6, 2008.

BACKGROUND OF THE INVENTION

Intracellular receptors (IR's) are a class of structurally relatedproteins involved in the regulation of gene expression. The steroidhormone receptors are a subset of this superfamily whose natural ligandsare typically comprised of endogenous steroids such as estradiol,progesterone, and cortisol. Man-made ligands to these receptors play animportant role in human health and, of these receptors, theglucocorticoid receptor has an essential role in regulating humanphysiology and immune response. Steroids that interact with theglucocorticoid receptor have been shown to be potent anti-inflammatoryagents. The present invention is directed to a novel class of compoundsthat are selective glucocorticoid receptor modulators that have potentanti-inflammatory and immunosuppressive activity and possess advantagesover steroidal glucocorticoid ligands with respect to side effects,efficacy, toxicity and/or metabolism.

SUMMARY OF THE INVENTION

The present invention is directed to hexahydrocyclopenty[f]indazolesulfonamides and derivatives thereof as selective glucocorticoidreceptor ligands useful for treating a variety of autoimmune andinflammatory diseases or conditions. Pharmaceutical compositions andmethods of use are also included.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect the invention encompasses compounds of Formula I

or a pharmaceutically acceptable salt thereof, wherein

-   R¹ is selected from the group consisting of:    -   (a) C₁₋₆alkyl, optionally mono-, di- or tri substituted with        substituents independently selected from        -   (1) halo,        -   (2) —CF₃,        -   (3) hydroxyl,        -   (4) oxo,        -   (5) —CN, and        -   (6) pyridine,    -   (b) C₂₋₆alkenyl, optionally mono-, di- or tri substituted with        fluoro,    -   (c) —C₃₋₆cycloalkyl,    -   (d) —C₁₋₂alkylC₃₋₆cycloalkyl,    -   (e) heterocycle,    -   (f) —C₁₋₂alkylheterocycle,    -   (g) aryl selected from phenyl or naphthyl,    -   (h) —C₁₋₂alkylaryl,    -   (i) —C₂₋₄alkenylaryl,    -   (j) heteroaryl,    -   (k) —C₁₋₂alkylheteroaryl,    -   (l) —Oheteroaryl,    -   (m) —OC₁₋₆alkyl optionally mono-, di- or tri substituted with        fluoro,    -   (n) —C1-4alkyl-O—C1-6alkyl, optionally substituted with hydroxy,        or —O—S(O)₂—C₁₋₂alkyl-CF₃,    -   (O) —OC₃₋₆cycloalkyl, and    -   (p) —Oaryl,        wherein the heteroaryl, aryl and heterocycle of choices (e),        (f), (g), (h), (i), (j), (k), (l), and (p) are optionally        substituted with 1, 2 or 3 substituents independently selected        from the group consisting of    -   (1) hydroxyl,    -   (2) halo,    -   (3) —CN,    -   (4) —CF₃,    -   (5) —C₁₋₄alkyl,    -   (6) —OC₁₋₄alkyl,    -   (7) —O—CH₂CF₃,    -   (8) heteroaryl selected from pyrazole, thiophene, imidazole, and        oxazole, optionally substituted with 1, 2 or 3 substitutents        independently selected from methyl, CF₃ and halo,    -   (9) —NH—OCH₃,    -   (10) phenyl,    -   (11) —O-phenyl,    -   (12) pyridine,    -   (13) —O-pyridine,    -   (14) —NH—C(O)—NH—CH₃,    -   (15) —NH—C(O)—C₁₋₄alkyl,    -   (16) —NH—C(O)—C₃₋₆cycloalkyl,    -   (17) —C₁₋₃alkyl-C(O)—OH,    -   (18) —C₁₋₃alkyl-C(O)—O—CH₃,    -   (19) —C(O)—NH₂,    -   (20) —C(O)—C₁₋₄alkyl-NH₂,    -   (21) —C(O)—NH—C₃₋₆cycloalkyl,    -   (22) —C(O)—OH,    -   (23) —C(O)—O—C₁₋₄alkyl,    -   (24) —C₁₋₂alkyl-heterocycle,    -   (25) —C₂₋₄alkenyl-C(O)-phenyl, and    -   (26) —O—S(O)₂—C₁₋₂alkyl-CF₃;-   R² is selected from the group consisting of:    -   (a) H,    -   (b) OH,    -   (c) C₁₋₈alkyl, optionally mono-, di- or tri substituted with        substituents independently selected from        -   (1) halo,        -   (2) hydroxyl,        -   (3) oxo,        -   (4) —CN,        -   (5) CHF₂,        -   (6) CF₃,        -   (7) pyridyl,        -   (8) —O—S(O)₂—CF₃, and        -   (9) —O—S(O)₂—C₁₋₂alkyl-CF₃,    -   (d) C₂₋₆alkenyl, optionally mono-, di- or tri substituted with        fluoro,    -   (e) —C₁₋₂alkylC₃₋₆cycloalkyl,    -   (f) heterocycle,    -   (g) —C₁₋₂alkylheterocycle,    -   (h) aryl selected from phenyl or naphthyl,    -   (i) —C₁₋₃alkylaryl,    -   (j) —C₂₋₄alkenylaryl,    -   (k) heteroaryl,    -   (l) —C₁₋₂alkylheteroaryl,    -   (m) —CH₂pyridyl, and    -   (O) —C1-4alkyl-O—C1-6alkyl, optionally substituted with hydroxy,        or —O—S(O)₂—C₁₋₂alkyl-CF₃,        wherein the cycloalkyl, heteroaryl, aryl and heterocycle of        choices (e), (f), (g), (h), (i), (j), (k), (l) and (m) are        optionally substituted with 1, 2 or 3 substituents independently        selected from the group consisting of    -   (1) hydroxyl,    -   (2) halo,    -   (3) —CN,    -   (4) —CF₃,    -   (5) —C₁₋₄alkyl,    -   (6) —OCH₃,    -   (7) —O—CH₂CF₃,    -   (8) heteroaryl selected from pyrazole, thiophene, imidazole, and        oxazole, optionally substituted with 1, 2 or 3 substitutents        independently selected from methyl, and halo,    -   (9) —NH—OCH₃,    -   (10) phenyl,    -   (11) —O-phenyl,    -   (12) pyridine,    -   (13) —O-pyridine,    -   (14) —NH—C(O)—NH—CH₃,    -   (15) —NH—C(O)—C₁₋₄alkyl,    -   (16) —NH—C(O)—C₃₋₆cycloalkyl,    -   (17) —C₁₋₃alkyl-C(O)—OH,    -   (18) —C₁₋₃ alkyl-C(O)—O—CH₃,    -   (19) —C(O)—NH₂,    -   (20) —C(O)—C₁₋₄alkyl-NH₂,    -   (21) —C(O)—NH—C₃₋₆cycloalkyl,    -   (22) —C(O)—OH,    -   (23) —C(O)—O—C₁₋₄alkyl,    -   (24) —C₁₋₂alkyl-heterocycle,    -   (25) —C₂₋₄alkenyl-C(O)-phenyl, and    -   (26) —O—S(O)₂—C₁₋₂alkyl-CF₃;-   R³ is selected from    -   (a) H,    -   (b) C₁₋₆alkyl,    -   (c) C₃₋₆cycloalkyl, and    -   (d) C₁₋₆-fluoroalkyl; and-   R⁴ is hydrogen or F.

Within this aspect is a genus of compounds wherein

R¹ is selected from the group consisting of:

-   -   (a) C₁₋₆alkyl, optionally mono-, di- or tri substituted with        substituents independently selected from        -   (1) halo selected from fluoro and chloro,        -   (2) —CF₃,        -   (3) hydroxyl, and        -   (4) pyridine,    -   (b) C₂₋₆alkenyl, optionally mono-, di- or tri substituted with        fluoro,    -   (c) —C₃₋₆cycloalkyl,    -   (d) —C₁₋₂alkylC₃₋₆cycloalkyl,    -   (e) heterocycle,    -   (f) —C₁₋₂alkylheterocycle,    -   (g) aryl selected from phenyl or naphthyl,    -   (h) —C₁₋₂alkylaryl,    -   (i) —C₂₋₄alkenylaryl,    -   (j) heteroaryl,    -   (k) —C₁₋₂alkylheteroaryl,    -   (l) —Oheteroaryl,    -   (m) —OC₁₋₆alkyl optionally mono-, di- or tri substituted with        fluoro,    -   (n) —C1-4alkyl-O—C1-6alkyl, optionally substituted with hydroxy,        or —O—S(O)₂—C₁₋₂alkyl-CF₃,    -   (O) —OC₃₋₆cycloalkyl, and    -   (p) —Oaryl,        wherein the heteroaryl, aryl and heterocycle of choices (e),        (f), (g), (h), (i), (j), (k), (l), and (p) are optionally        substituted with 1, 2 or 3 substituents independently selected        from the group consisting of    -   (1) hydroxyl,    -   (2) halo,    -   (3) —CN,    -   (4) —CF₃,    -   (5) —C₁₋₄alkyl,    -   (6) —OC₁₋₄alkyl.    -   (7) —O—CH₂CF₃,    -   (8) —NH—OCH₃,    -   (9) —NH—C(O)—NH—CH₃,    -   (10) —NH—C(O)—C₁₋₄alkyl,    -   (11) —NH—C(O)—C₃₋₆cycloalkyl,    -   (12) —C₁₋₃alkyl-C(O)—OH,    -   (13) —C₁₋₃ alkyl-C(O)—O—CH₃,    -   (14) —C(O)—NH₂,    -   (15) —C(O)—C₁₋₄alkyl-NH₂,    -   (16) —C(O)—NH—C₃₋₆cycloalkyl,    -   (17) —C(O)—OH,    -   (18) —C(O)—O—C₁₋₄alkyl,    -   (19) —C₁₋₂alkyl-heterocycle,    -   (20) —C₂₋₄alkenyl-C(O)-phenyl, and    -   (21) —O—S(O)₂—C₁₋₂alkyl-CF₃.

Within this genus, there is a sub-genus of compounds wherein

-   R¹ is selected from the group consisting of    -   (a) C₁₋₆alkyl, optionally mono-, di- or tri substituted with        substituents independently selected from        -   (1) halo selected from fluoro and chloro,        -   (2) —CF₃,        -   (3) hydroxyl, and        -   (4) pyridine,    -   (b) —C₃₋₆cycloalkyl,    -   (c) —C₁₋₂alkylC₃₋₆cycloalkyl,    -   (d) heterocycle,    -   (e) —C₁₋₂alkylheterocycle,    -   (f) aryl selected from phenyl or naphthyl,    -   (g) —C₁₋₂alkylaryl,    -   (h) heteroaryl,    -   (i) —C₁₋₂alkylheteroaryl,        wherein the heteroaryl, aryl and heterocycle of choices (d),        (e), (f), (g), (h) and (i) are optionally substituted with 1, 2        or 3 substituents independently selected from the group        consisting of    -   (1) halo,    -   (2) —CN,    -   (3) —CF₃,    -   (4) —C₁₋₄alkyl,    -   (5) —OC₁₋₄alkyl,    -   (6) —O—CH₂CF₃,    -   (7) —C(O)—NH₂, and    -   (8) —C(O)—O—C₁₋₄alkyl.

Within this sub-genus there is a class of compounds wherein

-   R¹ is selected from the group consisting of:    -   (a) C₁₋₆alkyl, optionally mono-, di- or tri substituted with        substituents independently selected from        -   (1) halo selected from fluoro and chloro,        -   (2) —CF₃,        -   (3) hydroxyl, and        -   (4) pyridine,    -   (b) aryl selected from phenyl or naphthyl,    -   (c) —C₁₋₂alkylaryl,    -   (d) heteroaryl, and    -   (e) —C₁₋₂alkylheteroaryl,        wherein the heteroaryl, aryl and heterocycle of choices (b),        (c), (d) and (e) are optionally substituted with 1, 2 or 3        substituents independently selected from the group consisting of    -   (1) halo, selected from Fluoro and Chloro    -   (2) —CF₃,    -   (3) —C₁₋₄alkyl,    -   (4) —OC₁₋₄alkyl,    -   (5) —C(O)—NH₂, and    -   (6) —C(O)—O—C₁₋₄alkyl.

Within this aspect there is a genus wherein

-   R² is selected from the group consisting of:    -   (a) H,    -   (b) OH,    -   (c) C₁₋₈alkyl, optionally mono-, di- or tri substituted with        substituents independently selected from        -   (1) halo,        -   (2) hydroxyl,        -   (3) oxo,        -   (4) —CN,        -   (5) CHF₂,        -   (6) CF₃,        -   (7) pyridyl, and        -   (8) —O—S(O)₂—C₁₋₂alkyl-CF₃;    -   (d) C₂₋₆alkenyl, optionally mono-, di- or tri substituted with        fluoro,    -   (e) —C₁₋₂alkylC₃₋₆cycloalkyl,    -   (f) heterocycle,    -   (g) —C₁₋₂alkylheterocycle,    -   (h) aryl selected from phenyl or naphthyl,    -   (i) —C₁₋₂alkylaryl,    -   (j) —C₂₋₄alkenylaryl,    -   (k) heteroaryl,    -   (l) —C₁₋₂alkylheteroaryl,    -   (m) —CH₂pyridyl,    -   (o) —C1-4alkyl-O—C1-6alkyl, optionally substituted with hydroxy,        or —O—S(O)₂—C₁₋₂alkyl-CF₃,        wherein the cycloalkyl, heteroaryl, aryl and heterocycle of        choices (e), (f), (g), (h), (i), (j), (k), (l) and (m) are        optionally substituted with 1, 2 or 3 substituents independently        selected from the group consisting of    -   (1) hydroxyl,    -   (2) halo,    -   (3) —CN,    -   (4) —CF₃,    -   (5) —C₁₋₄alkyl,    -   (6) —OCH₃,    -   (7) —O—CH₂CF₃,    -   (8) —NH—C(O)—NH—CH₃,    -   (9) —NH—C(O)—C₁₋₄alkyl,    -   (10) —NH—C(O)—C₃₋₆cycloalkyl,    -   (11) —C₁₋₃ alkyl-C(O)—OH,    -   (12) —C₁₋₃alkyl-C(O)—O—CH₃,    -   (13) —C(O)—NH₂,    -   (14) —C(O)—C₁₋₄alkyl-N142,    -   (15) —C(O)—NH—C₃₋₆cycloalkyl,    -   (16) —C(O)—OH,    -   (17) —C(O)—O—C₁₋₄alkyl,    -   (18) —C₁₋₂alkyl-heterocycle,    -   (19) —C₂₋₄alkenyl-C(O)-phenyl, and    -   (20) —O—S(O)2-C₁₋₂alkyl-CF₃.

Within this genus there is a sub-genus wherein

-   R² is selected from the group consisting of    -   (a) H    -   (b) OH,    -   (c) C₁₋₈alkyl, optionally mono-, di- or tri substituted with        substituents independently selected from        -   (1) halo,        -   (2) hydroxyl,        -   (3) oxo,        -   (4) —CN,        -   (5) CHF₂,        -   (6) CF₃, and        -   (7) —O—S(O)₂—C₁₋₂alkyl-CF₃;    -   (d) —C₁₋₂alkylC₃₋₆cycloalkyl,    -   (e) —C₁₋₂alkylheterocycle,    -   (f) aryl selected from phenyl or naphthyl,    -   (g) —C₁₋₂alkylaryl,    -   (h) heteroaryl,    -   (i) —C₁₋₂alkylheteroaryl,    -   (j) —C₁₋₄alkyl-O—CH₃,        wherein the cycloalkyl, heteroaryl, aryl and heterocycle of        choices (d), (e), (f), (g), (h) and (i) are optionally        substituted with 1, 2 or 3 substituents independently selected        from the group consisting of    -   (1) hydroxyl,    -   (2) halo,    -   (3) —CN,    -   (4) —CF₃,    -   (5) —C₁₋₄alkyl,    -   (6) —OCH₃,    -   (7) —O—CH₂CF₃,    -   (8) —NH—C(O)—NH—CH₃,    -   (9) —NH—C(O)—C1.4alkyl,    -   (10) —NH—C(O)—C₃₋₆cycloalkyl,    -   (11) —C₁₋₃alkyl-C(O)—OH,    -   (12) —C₁₋₃alkyl-C(O)—O—CH₃,    -   (13) —C(O)—NH₂,    -   (14) —C(O)—C₁₋₄alkyl-NH₂,    -   (15) —C(O)—NH—C₃₋₆cycloalkyl,    -   (16) —C(O)—OH,    -   (17) —C(O)—O—C₁₋₄alkyl,    -   (18) —C₁₋₂alkyl-heterocycle,    -   (19) —C₂₋₄alkenyl-C(O)-phenyl, and    -   (20) —O—S(O)₂—C₁₋₂alkyl-CF₃.

Within this sub-genus there is a class of compounds wherein

R² is selected from the group consisting of:

-   -   (a) H,    -   (b) OH,    -   (c) C₁₋₈alkyl, optionally mono-, di- or tri substituted with        substituents independently selected from        -   (1) halo,        -   (2) hydroxyl,        -   (3) CHF₂,        -   (4) CF₃, and        -   (5) —O—S(O)₂—C₁₋₂alkyl-CF₃;    -   (d) —C₁₋₂alkylC₃₋₆cycloalkyl,    -   (e) aryl selected from phenyl or naphthyl,    -   (f) —C₁₋₂alkylaryl,    -   (g) —C₁₋₂alkylheteroaryl,    -   (h) —C₁₋₄alkyl-O—CH₃,        wherein the cycloalkyl, heteroaryl, aryl and heterocycle of        choices (d), (e), (f), (g), (h) and (i) are optionally        substituted with 1, 2 or 3 substituents independently selected        from the group consisting of    -   (1) hydroxyl,    -   (2) halo,    -   (3) —CN,    -   (4) —CF₃,    -   (5) —C₁₋₄alkyl,    -   (6) —OCH₃,    -   (7) —O—CH₂CF₃, and    -   (8) —O—S(O)₂—C₁₋₂alkyl-CF₃.

Within this aspect there is a genus of compounds wherein

-   R³ is selected from    -   (a) H, and    -   (b) C₁₋₆alkyl.

Within this genus there is a sub-genus wherein

-   R³ is hydrogen.

Within this aspect there is a genus of compounds wherein:

-   R⁴ is F.

Within this aspect there is a genus of compounds of Formula II

or a pharmaceutically acceptable salt thereof wherein

-   R¹ is selected from the group consisting of:    -   (a) C₁₋₆alkyl, optionally mono-, di- or tri substituted with        substituents independently selected from        -   (1) halo selected from fluoro and chloro,        -   (2) —CF₃,        -   (3) hydroxyl, and        -   (4) pyridine,    -   (b) aryl selected from phenyl or naphthyl,    -   (c) —C₁₋₂alkylaryl,    -   (d) heteroaryl,    -   (e) —C₁₋₂alkylheteroaryl,        wherein the heteroaryl, aryl and heterocycle of choices (b),        (c), (d) and (e) are optionally substituted with 1, 2 or 3        substituents independently selected from the group consisting of    -   (1) halo, selected from fluoro and chloro,    -   (2) —CF₃,    -   (3) —C₁₋₄alkyl,    -   (4) —OC₁₋₄alkyl,    -   (5) —C(O)—NH₂, and    -   (6) —C(O)—O—C₁₋₄alkyl; and-   R² is selected from the group consisting of:    -   (a) H,    -   (b) OH,    -   (c) C₁₋₈alkyl, optionally mono-, di- or tri substituted with        substituents independently selected from        -   (1) halo,        -   (2) hydroxyl,        -   (3) CHF₂,        -   (4) CF₃, and        -   (5) —O—S(O)₂—C₁₋₂alkyl-CF₃;    -   (d) —C₁₋₂alkylC₃₋₆cycloalkyl,    -   (e) aryl selected from phenyl or naphthyl,    -   (f) —C₁₋₂alkylaryl,    -   (g) —C₁₋₂alkylheteroaryl,    -   (h) —C₁₋₄alkyl-O—CH₃,        wherein the cycloalkyl, heteroaryl, aryl and heterocycle of        choices (d), (e), (f), (g), (h) and (i) are optionally        substituted with 1, 2 or 3 substituents independently selected        from the group consisting of    -   (1) hydroxyl,    -   (2) halo,    -   (3) —CN,    -   (4) —CF₃,    -   (5) —C₁₋₄-alkyl, and    -   (6) —OCH₃.

Within this genus there is a sub-genus of compounds wherein

-   R¹ is selected from the group consisting of:    -   (a) C₁₋₆alkyl, optionally mono-, di- or tri substituted with        substituents independently selected from        -   (1) halo selected from fluoro and chloro,        -   (2) —CF₃,        -   (3) hydroxyl, and        -   (4) pyridine,    -   (b) aryl selected from phenyl or naphthyl,    -   (c) —C₁₋₂alkylaryl,    -   (d) heteroaryl, and    -   (e) —C₁₋₂alkylheteroaryl,        wherein the heteroaryl, aryl and heterocycle of choices (h),        (c), (d) and (e) are optionally substituted with 1, 2 or 3        substituents independently selected from the group consisting of    -   (1) halo, selected from Fluoro and Chloro    -   (2) —CF₃,    -   (3) —C₁₋₄alkyl,    -   (4) —OC₁₋₄alkyl,    -   (5) —C(O)—NH₂, and    -   (6) —C(O)—O—C₁₋₄alkyl; and-   R² is selected from the group consisting of:    -   (a) H,    -   (b) OH,    -   (c) C₁₋₈alkyl, optionally mono-, di- or tri substituted with        substituents independently selected from        -   (1) halo,        -   (2) hydroxyl,        -   (3) CHF₂,        -   (4) CF₃, and        -   (5) —O—S(O)₂—C₁₋₂alkyl-CF₃,    -   (d) —C₁₋₂alkylC₃₋₆cycloalkyl,    -   (e) aryl selected from phenyl or naphthyl,    -   (f) —C₁₋₂alkylaryl,    -   (g) —C₁₋₂alkylheteroaryl,    -   (h) —C₁₋₄alkyl-O—CH₃,        wherein the cycloalkyl, heteroaryl, aryl and heterocycle of        choices (d), (e), (f), (g), (h) and (i) are optionally        substituted with 1, 2 or 3 substituents independently selected        from the group consisting of    -   (1) halo,    -   (2) —CF₃,    -   (3) —C₁₋₄alkyl, and    -   (4) —OCH₃.    -   or a pharmaceutically acceptable salt thereof.

Another embodiment of the invention encompasses a pharmaceuticalcomposition comprising a compound of Formula I in combination with apharmaceutically acceptable carrier.

Another embodiment of the invention encompasses a method for treating aglucocorticoid receptor mediated disease or condition in a mammalianpatient in need of such treatment comprising administering the patient acompoud of Formula I in an amount that is effective for treating theglucocorticoid receptor mediated disease or condition.

Within this embodiment is encompassed the above method wherein theglucocorticoid receptor mediated disease or condition is selected fromthe group consisting of: tissue rejection, leukemias, lymphomas,Cushing's syndrome, acute adrenal insufficiency, congenital adrenalhyperplasia, rheumatic fever, polyarteritis nodosa, granulomatouspolyarteritis, inhibition of myeloid cell lines, immuneproliferation/apoptosis, HPA axis suppression and regulation,hypercortisolemia, stroke and spinal cord injury, hypercalcemia,hypergylcemia, acute adrenal insufficiency, chronic primary adrenalinsufficiency, secondary adrenal insufficiency, congenital adrenalhyperplasia, cerebral edema, thrombocytopenia, Little's syndrome,obesity, metabolic syndrome, inflammatory bowel disease, systemic lupuserythematosus, polyartitis nodosa, Wegener's granulomatosis, giant cellarteritis, rheumatoid arthritis, juvenile rheumatoid arthritis, uveitis,hay fever, allergic rhinitis, urticaria, angioneurotic edema, chronicobstructive pulmonary disease, asthma, tendonitis, bursitis, Crohn'sdisease, ulcerative colitis, autoimmune chronic active hepatitis, organtransplantation, hepatitis, cirrhosis, inflammatory scalp alopecia,panniculitis, psoriasis, discoid lupus erythematosus, inflamed cysts,atopic dermatitis, pyoderma gangrenosum, pemphigus vulgaris, buflouspemphigoid, systemic lupus erythematosus, dermatomyositis, herpesgestationis, eosinophilic fasciitis, relapsing polychondritis,inflammatory vasculitis, sarcoidosis, Sweet's disease, type I reactiveleprosy, capillary hemangiomas, contact dermatitis, atopic dermatitis,lichen planus, exfoliative dermatitus, erythema nodosum, acne,hirsutism, toxic epidenual necrolysis, erythema multiform, cutaneousT-cell lymphoma, Human Immunodeficiency Virus (HIV), cell apoptosis,cancer, Kaposi's sarcoma, retinitis pigmentosa, cognitive performance,memory and learning enhancement, depression, addiction, mood disorders,chronic fatigue syndrome, schizophrenia, sleep disorders, and anxiety.

Another embodiment of the invention encompasses a method of selectivelymodulating the activation, repression, agonism and antagonism effects ofthe glucocorticoid receptor in a mammal comprising administering to themammal a compound of Formula I in an amount that is effective tomodulate the glucocorticoid receptor.

Exemplifying the invention are the compounds of the Examples disclosedhereunder.

Definitions

The invention is described using the following definitions unlessotherwise indicated.

“Alkyl”, as well as other groups having the prefix “alk”, such asalkoxy, alkanoyl, means carbon chains which may be linear or branched orcombinations thereof. Examples of alkyl groups include methyl, ethyl,propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl,octyl, nonyl, and the like.

“Fluoroalkyl” means alkyl as defined above wherein one or more of thehydrogen atoms are replaced with a fluoro atom, up to the maximum numberof substitutable positions.

“Alkenyl” means carbon chains which contain at least one carbon-carbondouble bond, and which may be linear or branched or combinationsthereof. Examples of alkenyl include vinyl, allyl, isopropenyl,pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl,and the like.

“Alkynyl” means carbon chains which contain at least one carbon-carbontriple bond, and which may be linear or branched or combinationsthereof. Examples of alkynyl include ethynyl, propargyl,3-methyl-1-pentynyl, 2-heptynyl and the like.

“Cycloalkyl” means mono-, bi- or tri-cyclic saturated carbocyclic ringshaving the indicated number of carbon atoms. The term also includesmonocyclic rings fused to an aryl group in which the point of attachmentis on the non-aromatic portion. Examples of cycloalkyl includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,tetrahydronaphthyl, decahydronaphthyl, indanyl, adamantanyl and thelike.

“Aryl” means mono- or bicyclic aromatic rings containing only carbonatoms. The term also includes aryl group fused to a monocycliccycloalkyl or monocyclic heterocyclyl group in which the point ofattachment is on the aromatic portion. Examples of aryl include phenyl,naphthyl, indanyl, indenyl, tetrahydronaphthyl, 2,3-dihydrobenzofuranyl,dihydrobenzopyranyl, 1,4-benzodioxanyl, and the like.

“Heteroaryl” means a mono- or bicyclic aromatic ring containing at leastone heteroatom selected from N, O and S, with each ring containing 5 to6 atoms. Examples of heteroaryl include pyrrolyl, isoxazolyl,isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl,thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl,thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzoxazolyl,benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl,furo(2,3-b)pyridyl, quinolyl, indolyl, isoquinolyl, and the like.

“Heterocyclyl” or “heterocycle” means mono- or bicyclic saturated ringscontaining at least one heteroatom selected from N, S and O, each ofsaid ring having from 3 to 10 atoms in which the point of attachment maybe carbon or nitrogen. The term also includes monocyclic heterocyclefused to an aryl or heteroaryl group in which the point of attachment ison the non-aromatic portion. Examples of “heterocyclyl” includepyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl,2,3-dihydrofuro(2,3-b)pyridyl, benzoxazinyl, tetrahydrohydroquinolinyl,tetrahydroisoquinolinyl, dihydroindolyl, and the like. The term alsoincludes partially unsaturated monocyclic rings that are not aromatic,such as 2- or 4-pyridones attached through the nitrogen orN-substituted-(1H,3H)-pyrimidine-2,4-diones (N-substituted uracils).

Abbreviations

The following abbreviations have the indicated meanings:

AIBN = 2.2′-azobisisobutyronitrile B.P. = benzoyl peroxide Bn = benzylCCl₄ = carbon tetrachloride D = —O(CH₂)₃O— DAST = diethylamine sulfurtrifluoride DCC = dicyclohexyl carbodiimide DCI =1-(3-dimethylaminopropy1)-3-ethyl carbodiimide DEAD = diethylazodicarboxylate DIBAL = diisobutyl aluminum hydride DME = ethyleneglycol dimethylether DMAP = 4-(dimethylamino)pyridine DMF =N,N-dimethylformamide DMSO = dimethyl sulfoxide Et₃N = triethylamine LDA= lithium diisopropylamide m-CPBA = metachloroperbenzoic acid NBS =N-bromosuccinimide NSAID = non-steroidal anti-inflammatory drug PCC =pyridinium chlorochromate PDC = pyridinium dichromate Ph = phenyl 1,2-Ph= 1,2-benzenediy1 Pyr = pyridinediyl Qn = 7-chloroquinolin-2-yl R^(s) =—CH₂SCH₂CH₂Ph r.t. = room temperature rac. = racemic THF =tetrahydrofuran THP = tetrahydropyran-2-ylAlkyl group abbreviations

Me = methyl Et = ethyl n-Pr = normal propyl i-Pr = isopropyl n-Bu =normal butyl i-Bu = isobutyl s-Bu = secondary butyl t-Bu = tertiarybutyl c-Pr = cyclopropyl c-Bu = cyclobutyl c-Pen = cyclopentyl c-Hex =cyclohexylOptical Isomers—Diastereomers—Geometric Isomers—Tautomers

Compounds of Formula I contain one or more asymmetric centers and canthus occur as racemates and racemic mixtures, single enantiomers,diastereomeric mixtures and individual diastereomers. The presentinvention is meant to comprehend all such isomeric forms of thecompounds of Formula I.

Some of the compounds described herein contain olefinic double bonds,and unless specified otherwise, are meant to include both E and Zgeometric isomers.

Some of the compounds described herein may exist with different pointsof attachment of hydrogen, referred to as tautomers. Such an example maybe a ketone and its enol form known as keto-enol tautomers. Theindividual tautomers as well as mixture thereof are encompassed withcompounds of Formula I.

Compounds of the Formula I may be separated into diastereoisomeric pairsof enantiomers by, for example, fractional crystallization from asuitable solvent, for example MeOH or EtOAc or a mixture thereof. Thepair of enantiomers thus obtained may be separated into individualstereoisomers by conventional means, for example by the use of anoptically active amine as a resolving agent or on a chiral HPLC column.

Alternatively, any enantiomer of a compound of the general Formula I orIa may be obtained by stereospecific synthesis using optically purestarting materials or reagents of known configuration.

Salts

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids includinginorganic or organic bases and inorganic or organic acids. Salts derivedfrom inorganic bases include aluminum, ammonium, calcium, copper,ferric, ferrous, lithium, magnesium, manganic salts, manganous,potassium, sodium, zinc, and the like. Particularly preferred are theammonium, calcium, magnesium, potassium, and sodium salts. Salts derivedfrom pharmaceutically acceptable organic non-toxic bases include saltsof primary, secondary, and tertiary amines, substituted amitiesincluding naturally occurring substituted amines, cyclic amines, andbasic ion exchange resins, such as arginine, betaine, caffeine, choline,N,N′-dibenzylethylenediamine, diethylamine, 2-diethyl-aminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine,histidine, hydrabamine, isopropylamine, lysine, methyl-glucamine,morpholine, piperazine, piperidine, polyamine resins, procaine, purines,theobromine, triethylamine, trimethylamine, tripropylamine,tromethamine, and the like.

When the compound of the present invention is basic, salts may beprepared from pharmaceutically acceptable non-toxic acids, includinginorganic and organic acids. Such acids include acetic, benzenesulfonic,benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic,glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic,phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, andthe like. Particularly preferred are citric, hydrobromic, hydrochloric,maleic, phosphoric, sulfuric, and tartaric acids.

Dose Ranges

It will be understood that, as used herein, references to the compoundsof Formula I are meant to also include the pharmaceutically acceptablesalts.

The magnitude of prophylactic or therapeutic dose of a compound ofFormula I will, of course, vary with the nature and the severity of thecondition to be treated and with the particular compound of Formula Iand its route of administration. It will also vary according to avariety of factors including the age, weight, general health, sex, diet,time of administration, rate of excretion, drug combination and responseof the individual patient. In general, the daily dose from about 0.001mg to about 100 mg per kg body weight of a mammal, preferably 0.01 mg toabout 10 mg per kg. On the other hand, it may be necessary to usedosages outside these limits in some cases.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, aformulation intended for oral administration to humans may contain fromabout 0.5 mg to about 5 g of active agent compounded with an appropriateand convenient amount of carrier material which may vary from about 5 toabout 95 percent of the total composition. Dosage unit forms willgenerally contain from about 1 mg to about 2 g of an active ingredient,typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg,800 mg, or 1000 mg.

Pharmaceutical Compositions

For the treatment of glucocorticoid receptor mediated diseases thecompound of Formula I may be administered orally, topically,parenterally, by inhalation spray or rectally in dosage unitformulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes subcutaneous, intravenous, intramuscular, intrasternalinjection or infusion techniques. In addition to the treatment ofwarm-blooded animals such as mice, rats, horses, cattle, sheep, dogs,cats, etc., the compound of the invention is effective in the treatmentof humans.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, solutions, aqueous or oily suspensions, dispersible powders orgranules, emulsions, hard or soft capsules, syrups or elixirs.Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavouringagents, colouring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example, magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed. They may also becoated by the technique described in the U.S. Pat. Nos. 4,256,108;4,166,452; and 4,265,874 to form osmotic therapeutic tablets for controlrelease.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredients is mixed withwater-miscible solvents such as propylene glycol, PEGs and ethanol, oran oil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active material in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more colouringagents, one or more flavouring agents, and one or more sweeteningagents, such as sucrose, saccharin or aspartame.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavouring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavouring and colouringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof an oil-in-water emulsion. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavouring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavouring and colouringagents. The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example as a solution in 1,3-butane diol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. Cosolvents suchas ethanol, propylene glycol or polyethylene glycols may also be used.In addition, sterile, fixed oils are conventionally employed as asolvent or suspending medium. For this purpose any bland fixed oil maybe employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables.

The compounds of Formula I may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritatingexcipient which is solid at ambient temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials are cocoa butter and polyethylene glycols.

For topical use, creams, ointments, gels, solutions or suspensions,etc., containing a compound of Formula I are employed. (For purposes ofthis application, topical application shall include mouth washes andgargles.) Topical formulations may generally be comprised of apharmaceutical carrier, cosolvent, emulsifier, penetration enhancer,preservative system, and emollient.

Utilities

The ability of the compounds of Formula I to selectively modulateglucocorticoid receptors makes them useful for treating, preventing orreversing the progression of a variety of inflammatory and autoimmunediseases and conditions. Thus, the compounds of the present inventionare useful to treat, prevent or ameliorate the following diseases orconditions: inflammation, tissue rejection, auto-immunity, variousmalianancies, such as leukemias and lymphomas, Cushing's syndrome, acuteadrenal insufficiency, congenital adrenal hyperplasia, rheumatic fever,polyarteritis nodosa, granulomatous polyarteritis, inhibition of myeloidcell lines, immune proliferation/apoptosis, HPA axis suppression andregulation, hypercortisolemia, stroke and spinal cord injury,hypercalcemia, hypergylcemia, acute adrenal insufficiency, chronicprimary adrenal insufficiency, secondary adrenal insufficiency,congenital adrenal hyperplasia, cerebral edema, thrombocytopenia,Little's syndrome, obesity and metabolic syndrome.

The compounds of the present invention are also useful for treating,preventing or reversing the progression of disease states involvingsystemic inflammation such as inflammatory bowel disease, systemic lupuserythematosus, polyartitis nodosa, Wegener's granulomatosis, giant cellarteritis, rheumatoid arthritis, juvenile rheumatoid arthritis, uveitis,hay fever, allergic rhinitis, urticaria, angioneurotic edema, chronicobstructive pulmonary disease, asthma, tendonitis, bursitis, Crohn'sdisease, ulcerative colitis, autoimmune chronic active hepatitis, organtransplantation, hepatitis, and cirrhosis.

The compounds of the present invention are useful for treating,preventing or reversing the progression of a variety of topical diseasessuch as inflammatory scalp alopecia, panniculitis, psoriasis, discoidlupus erythematosus, inflamed cysts, atopic dermatitis, pyodermagangrenosum, pemphigus vulgaris, buflous pernphigoid, systemic lupuserythematosus, dermatomyositis, herpes gestationis, eosinophilicfasciitis, relapsing polychondritis, inflammatory vasculitis,sarcoidosis, Sweet's disease, type I reactive leprosy, capillaryhemangiomas, contact dermatitis, atopic dermatitis, lichen planus,exfoliative dermatitus, erythema nodosum, acne, hirsutism, toxicepidermal necrolysis, erythema multiform, cutaneous T-cell lymphoma.

The compounds of the present invention are also useful in treating,preventing or reversing the progression of disease states associatedwith Human Immunodeficiency Virus (HIV), cell apoptosis, and cancerincluding, but not limited to, Kaposi's sarcoma, immune systemactivation and modulation, desensitization of inflammatory responses,IL-1 expression, natural killer cell development, lymphocytic leukemia,and treatment of retinitis pigmentosa. Cogitive and behavioral processesare also susceptible to glucocorticoid therapy where antagonists wouldpotentially be useful in the treatment of processes such as cognitiveperformance, memory and learning enhancement, depression, addiction,mood disorders, chronic fatigue syndrome, schizophrenia, stroke, sleepdisorders, and anxiety.

Preferably, the compounds of the invention are useful for treating thediseases or conditions set for the below.

-   1. Allergic States

Control of severe or incapacitating allergic conditions not responsiveto adequate trials of conventional treatment; seasonal or perennialallergic rhinitis; bronchial asthma; contact dermatitis; atopicdermatitis; serum sickness; and drug hypersensitivity reactions.

-   2. Rheumatic Disorders

As adjunctive therapy for short-term administration during an acuteepisode or exacerbation of: psoriatic arthritis; rheumatoid arthritisincluding juvenile rheumatoid arthritis (selected cases may requirelow-dosemaintenance therapy); ankylosing spondylitis; acute and subacutebursitis; acute nonspecific tenosynovitis; acute gouty arthritis;post-traumatic osteoarthritis; synovitis of osteoarthritis; andepicondylitis

-   3. Dermatologic Diseases

Pemphigus; bullous dermatitis herpetiformis; severe erythema multiforme(Stevens-Johnson syndrome); exfoliative dermatitis; mycosis fungoïdes;severe psoriasis; and severe seborrheic dermatitis.

-   4. Ophthalmic Diseases

Severe acute and chronic allergic and inflammatory processes involvingthe eye and its adnexa such as: allergic conjunctivitis; keratitis;allergic corneal marginal ulcers; herpes zoster ophthalmicus; iritis andiridocyclitis; chorioretinitis; anterior segment inflammation; diffuseposterior uveitis and choroiditis; optic neuritis; and sympatheticophthalmia.

-   5. Endocrine Disorders

Primary or secondary adrenocortical insufficiency; congenital adrenalhyperplasia; nonsuppurative thyroiditis; and hypercalcemia associatedwith cancer.

-   6. Respiratory Diseases

Symptomatic sarcoidosis; Löffler's syndrome not manageable by othermeans; berylliosis; fulminating or disseminated pulmonary tuberculosiswhen concurrently accompanied by appropriate antituberculouschemotherapy; and aspiration pneumonitis.

-   7. Hematologic Disorders

Idiopathic thrombocytopenic purpura in adults; secondarythrombocytopenia in adults; acquired (autoimmune) hemolytic anemia;erythroblastopenia (RBC anemia); and congenital (erythroid) hypoplasticanemia.

-   8. Neoplastic Diseases

For palliative management of: leukemias and lymphomas in adults; andacute leukemia of childhood.

-   9. Edematous States

To induce a diuresis or remission of proteinuria in the nephroticsyndrome without uremia, of the idiopathic type or that due to lupuserythematosus. Compounds of Formula I may be used to treat patients withcerebral edema from various causes. It may be used also in thepreoperative preparation of patients with increased intracranialpressure secondary to brain tumors, and also for palliation of patientswith inoperable or recurrent brain neoplasms, and in the management ofcerebral edema associated with neurosurgery. Some patients with cerebraledema due to head injury or pseudotumor cerebri also may benefit fromtherapy with compounds of Formula I.

-   10. Gastrointestinal Diseases

During a critical period of the disease in: ulcerative colitis andregional enteritis.

-   11. Miscellaneous

Tuberculous meningitis with subarachnoid block or impending block whenconcurrently accompanied by appropriate antituberculous chemotherapy;Trichinosis with neurologic or myocardial involvement; During anexacerbation or as maintenance therapy in selected cases of: Systemiclupus erythematosus and acute rheumatic carditis; in combination withondansetron for the management of nausea and vomiting associated withcisplatin and non-cisplatin emetogenic chemotherapy.

Combination Therapy

The invention also encompasses a method for treating a glucocorticoidreceptor mediated disease comprising concomitantly administering to apatient in need of such treatment a compound of Formula I and one oradditional more agents. For treating or preventing asthma or chronicobstructive pulmonary disease, the compounds of Formula I may becombined with one or more agents selected from the group consisting of:θ-agonists (e.g., salmeterol), theophylline, anticholinergics (e.g.,atropine and ipratropium bromide), cromolyn, nedocromil and leukotrienemodifiers (e.g., montelukast). For treating or preventing inflammation,the compounds of Formula I may be combined with one or the following: asalicylate, including acetylsalicylic acid, a non-steroidalantiinflammatory drug, including indomethacin, sulindac, mefenamic,meclofenamic, tolfenamic, tolmetin, ketorolac, dicofenac, ibuprofen,naproxen, fenoprofen, ketoprofen, flurbiprofin and oxaprozin, a TNFinhibitor, including etanercept and infliximab, an IL-1 receptorantagonist, a cytotoxic or immunosuppressive drug, includingmethotrexate, leflunomide, azathioprine and cyclosporine, a goldcompound, hydroxychloroquine or sulfasalazine, penicillamine,darbufelone, and a p38 kinase inhibitor. The compound of Formula I mayalso be used in combination with bisphonates such as alendronate totreat a glucocorticoid mediated disease and simultaneously inhibitosteoclast-mediated bone resorption.

Methods of Synthesis and Examples

The invention will now be illustrated by the following non-limitingexamples in which, unless stated otherwise:

-   (i) all operations were carried out at room or ambient temperature,    that is, at a temperature in the range 18-25° C.,-   (ii) evaporation of solvent was carried out using a rotary    evaporator under reduced pressure (600-4000 pascals: 4.5-30 mm. Hg)    with a bath temperature of up to 60° C.,-   (iii) the course of reactions was followed by thin layer    chromatography (TLC) and reaction times are given for illustration    only;-   (iv) melting points are uncorrected and indicates decomposition; the    melting points given are those obtained for the materials prepared    as described; polymorphism may result in isolation of materials with    different melting points in some preparations;-   (v) the structure and purity of all final products were assured by    at least one of the following techniques: TLC, mass spectrometry,    nuclear magnetic resonance (NMR) spectrometry or microanalytical    data;-   (vi) yields are given for illustration only;-   (vii) when given, NMR data is in the form of delta (δ) values for    major diagnostic protons, given in parts per million (ppm) relative    to tetramethylsilane (TMS) as internal standard, determined at 500    MHz or 600 MHz using the indicated solvent; conventional    abbreviations used for signal shape are: s. singlet; d. doublet; t.    triplet; m. multiplet; br. broad; etc.: in addition “Ar” signifies    an aromatic signal;-   (viii) chemical symbols have their usual meanings; the following    abbreviations have also been used v (volume), w (weight), b.p.    (boiling point), m.p. (melting point), L (liter(s)), mL    (milliliters), g (gram(s)), mg (milligrams(s)), mol (moles), mmol    (millimoles), eq (equivalent(s)).    Methods of Synthesis and Examples

Compounds of the invention can be synthesized by following the followinggeneral synthetic scheme.

The invention will now be illustrated by the following non-limitingexamples in which, unless stated otherwise:

(i) all operations were carried out at room or ambient temperature, thatis, at a temperature in the range 18-25° C.,

(ii) evaporation of solvent was carried out using a rotary evaporatorunder reduced pressure (600-4000 pascals: 4.5-30 mm. Hg) with a bathtemperature of up to 60° C.,

(iii) the course of reactions was followed by thin layer chromatography(TLC) and reaction times are given for illustration only;

(iv) melting points are uncorrected and ‘d’ indicates decomposition; themelting points given are those obtained for the materials prepared asdescribed; polymorphism may result in isolation of materials withdifferent melting points in some preparations;

(v) the structure and purity of all final products were assured by atleast one of the following techniques: TLC, mass spectrometry, nuclearmagnetic resonance (NMR) spectrometry or microanalytical data;

(vi) yields are given for illustration only;

(vii) when given, NMR data is in the form of delta (δ) values for majordiagnostic protons, given in parts per million (ppm) relative totetramethylsilane (TMS) as internal standard, determined at 500 MHz or600 MHz using the indicated solvent; conventional abbreviations used forsignal shape are: s. singlet; d. doublet; t. triplet; m. multiplet; br.broad; etc.: in addition “Ar” signifies an aromatic signal;

(viii) chemical symbols have their usual meanings; the followingabbreviations have also been used v (volume), w (weight), b.p. (boilingpoint), imp, (melting point), L (liter(s)), L (milliliters), g(gram(s)), mg (milligrams(s)), mol (moles), mmol (millimoles), eq(equivalent(s)).

EXAMPLE 1N-{[(4αR,5S)-1-(4-Fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-1-pyridin-3-yl-N-(2-pyridin-2-ylethyl)methanesulfonamide(1-8)

(7α′S)-7α′-Methyl-2′,3′,7′,7α′-tetrahydrospiro[1,3-dioxolane-2,1′-inden]-5′(6′H)-one(1-2) Ethylene glycol (12.2 mL, 219 mmol) and p-toluenesulfonic acidmonohydrate (4.40 g, 25.6 mmol) were added to a solution ofHajos-Parrish Ketone (See Organic Syntheses, Coll. Vol. 7, p. 363; Vol63, p. 26) (1-1, 60.0 g, 365 mmol) in 2-ethyl-2-methyl-1,3-dioxolan (46mL) and the resulting solution stirred at ambient temperature for 24hours. The reaction was poured into saturated aqueous NaHCO₃ solution (1L) and the crude product extracted with EtOAc (x3). The combined organicextracts were dried over anhydrous MgSO₄ and the solvent removed invacuo. Purification by flash chromatography on 1.5 kg of silica, elutingwith a gradient of 0-70% EtOAc in hexanes afforded 48.5 g, 64% of 1-2 asa clear viscous oil.

MS (ESI): m/z=209.3 (MH⁺).

(7α′S)-7α′-Methyl-5′-oxo-2′,3′,5′,6′,7′,7α′-hexahydrospiro[1,3-dioxolane-2,1′-indene]-6′-carbaldehyde(1-3)

A 1.5 M solution of lithium diisopropylamide mono(tetrahydrofuran) incyclohexane (465 mL, 0.698 mol) was added to a solution of 1-2 (48.5 g,0.233 mol) in diethyl ether (930 mL) at −78° C. and the resultingsolution stirred at this temperature for 1 hour to afford a thicksuspension. Methyl formate (86.6 mL, 1.40 mol) was added dropwise overabout 30 min and the resulting suspension stirred at −78° C. for 5hours. The reaction was quenched at −78° C. with 1 M aqueous HClsolution (3 L) and the aqueous layer checked to ensure it was acidic.The crude product was extracted with EtOAc (x3) and the combined organicextracts were dried over anhydrous MgSO₄ and the solvent removed invacuo to afforded 60 g of crude 1-3 (74% pure) as a tan viscous oil thatwas used directly in the next step without purification.

MS (ESI): m/z=237.3 (MH⁺).

(4αS)-1-(4-Fluorophenyl)-4α-methyl-4,4α,6,7-tetrahydrocyclopenta[f]indazol-5(1H)-one(1-5)

Sodium acetate (38.2 g, 0.465 mol) was added to a solution of crude 1-3(60 g), p-fluorophenylhydrazine hydrochloride (47.3 g, 0.291 mol) andacetic acid (66.6 mL, 1.16 mol) in toluene (465 mL) and the resultingsuspension heated at 100° C. for 1 hour. The reaction was cooled toambient temperature, diluted with EtOAc, and washed carefully (CO₂evolution!) with aqueous 5% w/v NaHCO₃ solution (2×μL), then dried overanhydrous MgSO₄ and concentrated to afford a viscous brown oil. Thecrude oil was dissolved in THF (1 L) and aqueous 6M HCl (155 mL) wasadded and the resulting solution was heated to 65° C. for 3.5 hours. Theresulting solution was cooled to ambient temperature, and poured slowlyinto aqueous 5% w/v NaHCO₃ solution (CO₂ evolution!), and the crudeproduct was extracted with EtOAc (x3). The combined organic extractswere dried over anhydrous MgSO₄ and the solvent removed in vacuo.Purification by flash chromatography on 1.5 kg of silica, eluting with agradient of 0-50% EtOAc in hexanes afforded 48.3 g of 1-5, 74% from 1-3,as a viscous brown oil that solidified on standing for several days.

MS (ESI): m/z=2833 (MH⁺).

(4αR,5S)-1-(4-Fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazole-5-carbaldehyde(1-6)

A 1.6 M solution of nBuLi in hexanes (6.4 mL, 16.0 mmol) was added to asolution of diethyl isocyanomethylphosphonate (2.6 mL, 16.0 mmol) inanhydrous THF (30 mL) at −78° C. and the resulting solution stirred atthis temperature for 30 min. A solution of 1-5 (3.0 g, 10.6 mmol) inanhydrous THF (10 mL) was added dropwise over about 20 min and theresulting solution was stirred at −78° C. for 1 hour, then warmeddirectly to ambient temperature and stirred for a further 1 hour. Thereaction was quenched with saturated aqueous ammonium chloride solution,and the crude product was extracted with EtOAc (3×). The combinedorganic extracts were dried over anhydrous MgSO₄ and the solvent removedin vacuo. The vinyl isocyanate intermediate was dissolved in diethylether (50 mL) and 4M aqueous HCl (30 mL) was then added and the biphasicmixture was stirred at ambient temperature for 12 hours. The reactionwas quenched with 1M aqueous HCl, and the crude product was extractedwith EtOAc (3×). The combined organic extracts were dried over anhydrousMgSO₄ and the solvent removed in vacuo. This afforded 2.95 g, 94% of theproduct 1-6 as a thick, red oil.

MS (ESI); m/z=297.2 (MH⁺).

N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-2-pyridin-2-ylethanamine)(1-7)

Sodium triacetoxyborohydride (7.15 g, 33.7 mmol) was added to a solutionof 1-6 (5.0 g, 16.87 mmol), 2-(2-aminoethyl)pyridine (2.019 ml, 16.87mmol) and acetic acid (0.966 ml, 16.87 mmol) in dichloromethane (15 mL)at room temperature. The reaction mixture was stirred at roomtemperature for 2 hours and until LC/MS showed the reaction is complete.The reaction was quenched by the addition of a saturated solution ofsodium bicarbonate (25 mL) and extracted with dichloromethane (100 mL).The organic layer was washed with a 1N aqueous solution of sodiumhydroxide, dried over anhydrous MgSO₄ and the solvent removed in vacuo.This afforded 5.8 g, 85% of the product 1-7 as a brown oil which wasused without further purification.

MS (ESI): m/z=403.3 (MH⁺).

N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-1-pyridin-3-yl-N-(2-pyridin-2-ylethyl)methanesulfonamide(1-8)

Pyridin-3-ylmethanesulfonyl chloride (2.148 g, 6.29 mmol) was added to asolution of 1-7 (2.53 g, 6.29 mmol) and triethylamine (0.876 ml, 6.29mmol) at room temperature in dichloromethane (15 mL). The reactionmixture was stirred at room temperature for one hour and until LC/MSshowed the reaction is complete. The solvent was removed in vacuo andthe crude product was purified by reverse phase HPLC(C-18, 5-50%acetonitrile in water) which afforded 1.5 g, 42% of the product as ayellow solid.

HRMS (APCI): m/z=558.2311 (MH⁺).

The following examples were prepared following the general syntheticscheme and procedures analogous to the examples described above.

Ex. STRUCTURE NAME M + 1 2

N-(cyclopropylmethyl)-2-fluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5- yl]methyl}benzenesulfonamide 492.2429 3

N-allyl-2-fluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7- hexahydrocyclopenta[f]indazol-5-yl]methyl}benzenesulfonamide 470.1839 4

N-(cyclopropylmethyl)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-2-(trifluoromethyl)benzenesulfonamide 560.1991 5

2-chloro-N-(cyclopropylmethyl)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-5-(trifluoromethyl)benzenesulfonamide 594.1595 6

N-{4-[((cyclopropylmethyl){[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7- hexahydrocyclopenta[f]indazol-5-yl]methyl}amino)sulfonyl]phenyl}acetamide 549.2338 7

(5-chloro-N-(cyclopropylmethyl)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-1,3-dimethyl-1H-pyrazole-4-sulfonamide 544.195 8

N-(cyclopropylmethyl)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-7- sulfonamide 563.2486 9

N-(cyclopropylmethyl)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-4- pentylbenzenesulfonamide562.291 10

N-(cyclopropylmethyl)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7- hexahydrocyclopenta[f]indazol-5-yl]methyl}biphenyl-4-sulfonamide 568.2433 11

N-(cyclopropylmethyl)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-3,5-dimethylisoxazole-4-sulfonamide 511.2178 12

2-chloro-N-(cyclopropylmethyl)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5- yl]methyl}benzenesulfonamide 526.173713

(E)-N-(cyclopropylmethyl)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-2- phenylethylenesulfonamide518.2279 14

2-chloro-N-(cyclopropylmethyl)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-4-{[(methylamino)carbonyl]amino}- benzenesulfonamide 598.2054 15

3-chloro-N-(cyclopropylmethyl)-4-fluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}benzenesulfonamide 544.164 16

N-(2-cyanoethyl)-2-fluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7- hexahydrocyclopenta[f]indazol-5-yl]methyl}benzenesulfonamide 508.595 17

2-fluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α- methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-hydroxyethyl)benzenesulfonamide 499.584 18

methyl 2-[((cyclopropylmethyl){[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7- hexahydrocyclopenta[f]indazol-5yl]methyl}amino)sulfonyl]benzoate 549.67 19

3-chloro-4-fluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-hydroxyethyl)benzenesulfonamide 534.029 20

3-chloro-N-(cyanomethyl)-4-fluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}benzenesulfonamide 529.013 21

N-(cyclopropylmethyl)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-1- phenylmethanesulfonamide505.66 22

2-chloro-N-(cyclopropylmethyl)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5- yl]methyl}benzenesulfonamide 526.08 23

N-(cyanomethyl)-N-{[(4αR,5S)-1-(4- fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-5-methylisoxazole-4-sulfonamide 482.1626 24

4,5-dichloro-N-(cyanomethyl)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5- yl]methyl}thiophene-2-sulfonamide551.0498 25

N-(cyanomethyl)-3,4-difluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5- yl]methyl}benzenesulfonamide 513.152926

2,3-dichloro-N-(cyanomethyl)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5- yl]methyl}benzenesulfonamide 545.094227

4-chloro-N-(cyanomethyl)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-3-(trifluoromethyl)benzenesulfonamide 579.12 28

4-cyano-N-(cyanomethyl)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7- hexahydrocyclopenta[f]indazol-5-yl]methyl}benzenesulfonamide 502.1674 29

4-chloro-N-(cyanomethyl)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-2,5-dimethylbenzenesulfonamide 539.1655 30

N-(cyanomethyl)-N-{[(4αR,5S)-1-(4- fluorophenyl}-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-1-[3-(trifluoromethyl)phenyl]methanesulfonamide 559.1739 31

N-(cyanomethyl)-N-{[(4αR,5S)-1-(4- fluorophenyl}-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-5-methylthiophene-2-sulfonamide 497.1439 32

N-(cyanomethyl)-N-{[(4αR,5S)-1-(4- fluorophenyl}-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4- sulfonamide 549.1646 33

(4αR,5S)-5-({(cyanomethyl)[(2,5-dimethyl-3-furyl)sulfonyl]amino}methyl)-1-(4- fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-2-ium 495.1826 34

methyl 3-[((cyanomethyl){[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7- hexahydrocyclopenta[f]indazol-5-yl]methyl}amino)sulfonyl]thiophene-2- carboxylate 541.1336 35

(N-(cyanomethyl)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-5-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5- yl]thiophene-2-sulfonamide631.1535 36

3-cyano-N-(cyanomethyl)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7- hexahydrocyclopenta[f]indazol-5-yl]methyl}benzenesulfonamide 502.1674 37

N-(cyanomethyl)-N-{[(4αR,5S)-1-(4- fluorophenyl}-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-1-methyl-1H-imidazole-4-sulfonamide 481.179 38

4-(3-chloro-2-cyanophenoxy)-N-(cyanomethyl)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}benzenesulfonamide 628.1536 39

N-(cyanomethyl)-N-{[(4αR,5S)-1-(4- fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-7- sulfonamide 548.2088 40

N-(cyanomethyl)-N-{[(4αR,5S)-1-(4- fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5- yl]methyl}naphthalene-1-sulfonamide527.1877 41

N-(cyanomethyl)-N-{[(4αR,5S)-1-(4- fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}- 2,5-bis(2,2,2-trifluoroethoxy)benzenesulfonamide 673.1648 42

N-(cyanomethyl)-N-{[(4αR,5S)-1-(4- fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5- yl]methyl}biphenyl-4-sulfonamide553.2036 43

N-(cyanomethyl)-2-fluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7- hexahydrocyclopenta[f]indazol-5-yl]methyl}benzenesulfonamide 495.1627 44

N-(cyanomethyl)-3,5-difluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5- yl]methyl}benzenesulfonamide 513.153245

N-(cyanomethyl)-N-{[(4αR,5S)-1-(4- fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-4-(pyridin-2-yloxy)benzenesulfonamide 570.1924 46

N-(cyanomethyl)-4-fluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7- hexahydrocyclopenta[f]indazol-5-yl]methyl}benzenesulfonamide 495.1627 47

N-(cyanomethyl)-2,4,5-trifluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5- yl]methyl}benzenesulfonamide 531.143548

N-(cyanomethyl)-N-{[(4αR,5S)-1-(4- fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5- yl]methyl}-1- phenylmethanesulfonamide491.188 49

N-(cyanomethyl)-N-{[(4αR,5S)-1-(4- fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5- yl]methyl}-2- methylbenzenesulfonamide491.1882 50

2-chloro-N-(cyanomethyl)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7- hexahydrocyclopenta[f]indazol-5-yl]methyl}benzenesulfonamide 511.1332 51

N-(cyanomethyl)-2,4-difluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5- yl]methyl}benzenesulfonamide 513.153352

5-chloro-N-(cyanomethyl)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-1,3-dimethyl-1H-pyrazole-4-sulfonamide 529.1551 53

N-(cyanomethyl)-N-{[(4αR,5S)-1-(4- fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5- yl]methyl}biphenyl-2-sulfonamide553.2022 54

N-(cyanomethyl)-N-{[(4αR,5S)-1-(4- fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-2-(trifluoromethyl)benzenesulfonamide 545.1587 55

2-cyano-N-(cyanomethyl)-N-{[4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7- hexahydrocyclopenta[f]indazol-5-yl]methyl}benzenesulfonamide 502.1672 56

N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-hydroxyethyl)-5- methylisoxazole-4-sulfonamide 487.179857

N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-hydroxyethyl)-5-(1,3-oxazol-5-yl)thiophene-2-sulfonamide 555.1515 58

4,5-dichloro-N-{[(4αR,5S)-1-(4-fluorophenyl)- 4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-hydroxyethyl)thiophene-2-sulfonamide 556.0681 59

3,4-dichloro-N-{[(4αR,5S)-1-(4-fluorophenyl)- 4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-hydroxyethyl)benezenesulfonamide 518.1709 60

2-chloro-4-cyano-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-hydroxyethyl)benezenesulfonamide 541.1457 61

2,3-dichloro-N-{[(4αR,5S)-1-(4-fluorophenyl)- 4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-hydroxyethyl)benezenesulfonamide 550.1123 62

4-cyano-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α- methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-hydroxyethyl)benezenesulfonamide 507.1839 63

N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-hydroxyethyl)-1-[3-(trifluoromethyl)phenyl]methanesulfonamide 564.1907 64

N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-hydroxyethyl)-5- methylthiophene-2-sulfonamide 502.162165

N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-hydroxyethyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-sulfonamide 554.1837 66

N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-hydroxyethyl)-2,5- dimethylfuran-3-sulfonamide 500.202767

N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-hydroxyethyl)-5-[1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-yl]thiophene-2- sulfonamide 636.1738 68

3-cyano-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α- methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-hydroxyethyl)benezenesulfonamide 507.1851 69

4-(3-chloro-2-cyanophenoxy)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-hydroxyethyl)benzenesulfonamide 633.173 70

N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-hydroxyethyl)-2- (trifluoromethyl)benzenesulfonamide550.1763 71

N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-hydroxyethyl)-3,5- dimethylisoxazole-4-sulfonamide501.1948 72

3,5-dichloro-N-{[(4αR,5S)-1-(4-fluorophenyl)- 4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-hydroxyethyl)benezenesulfonamide 518.1747 73

methyl 2-{[{[(4αR,5S)-1-(4-fluorophenyl)-4α- methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}(2-hydroxyethyl)amino]sulfonyl}benzoate 540.1952 74

N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl- 1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-hydroxyethyl)-4-(pyridin-2- yloxy)benzenesulfonamide575.2119 75

N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl- 1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5- yl]methyl}-N-(2-hydroxyethyl)-1-phenylmethanesulfonamide 496.2065 76

2-chloro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α- methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N- (2-hydroxyethyl)-4-{[(methylamino)carbonyl]amino}- benzenesulfonamide 588.1819 77

N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl- 1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5- yl]methyl}-N-(2-hydroxyethyl)-2-methylbenzenesulfonamide 496.2049 78

2-cyano-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α- methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-hydroxyethyl)benzenesulfonamide 507.1856 79

N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl- 1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5- yl]methyl}-N-(2-hydroxyethyl)-4-phenoxybenzenesulfonamide 574.2178 80

2-chloro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α- methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N- (2-hydroxyethyl)-5-(trifluoromethyl)benzenesulfonamide 584.1395 81

2-chloro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α- methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-hydroxyethyl)benzenesulfonamide 516.1502 82

2,4-difluoro-N-{[(4αR,5S)- 1-(4-fluorophenyl)-4α- methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-hydroxyethyl)benzenesulfonamide 518.1703 83

5-chloro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α- methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-hydroxyethyl)-1,3-dimethyl-1H-pyrazole-4- sulfonamide 534.1721 84

N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl- 1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-hydroxyethyl)biphenyl-2- sulfonamide 558.2223 85

N-(4-{[{[(4αR,5S)-1-(4-fluorophenyl)-4α- methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5- yl]methyl}(2-hydroxyethyl)amino]sulfonyl}phenyl)acetamide 539.2108 86

2-fluoro-N-[2-(2-fluorophenyl)ethyl]-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}benzenesulfonamide 578.2068 87

N-[2-(2-fluorophenyl)ethyl]-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5- yl]methyl}propane-1-sulfonamide526.2322 88

N-[2-(2-fluorophenyl)ethyl]-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-1-[3-(trifluoromethyl)phenyl]methanesulfonamide 642.2192 89

2,2,2-trifluoro-N-[2-(2-fluorophenyl)ethyl]-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}ethanesulfonamide 566.1881 90

2-fluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α- methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-[2-(2-methoxyphenyl)ethyl]benzenesulfonamide 590.2265 91

2-fluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α- methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-[2-(4-methylphenyl)ethyl]benzenesulfonamide 574.2318 92

N-[2-(2-chlorophenyl)ethyl]-2-fluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}benzenesulfonamide 594.1773 93

2,2,2-trifluoro-N-[2-(2-fluorophenyl)ethyl]-N-{1-[(4αR)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5- yl]ethyl}ethanesulfonamide580.2 94

2-fluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α- methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-methoxyethyl)benzenesulfonamide 514.1972 95

N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl- 1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5- yl]methyl}-N-(2-methoxyethyl)propane-1-sulfonamide 462.2221 96

N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl- 1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5- yl]methyl}-N-(2-methoxyethyl)methanesulfonamide 434.1908 97

2,2,2-trifluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)- 4α-methyl-1,4,4α,5,6,7- hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-methoxyethyl)ethanesulfonamide 502.1782 98

N-[2-(2-fluorophenyl)ethyl]-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4- sulfonamide 632.2077 99

N-[2-(2-fluorophenyl)ethyl]-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-2-(trifluoromethyl)benzenesulfonamide 628.2016 100

2-chloro-N-[2-(2-fluorophenyl)ethyl]-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}benzenesulfonamide 594.1754 101

N-[2-(2-fluorophenyl)ethyl]-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7- hexahydrocyclopenta[f]indazol-5-yl]methyl}cyclopropanesulfonamide 524.2152 102

N-[2-(2-fluorophenyl)ethyl]-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7- hexahydrocyclopenta[f]indazol-5-yl]methyl}butane-1-sulfonamide 540.2466 103

N-[2-(2-fluorophenyl)ethyl]-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-2-methylpropane-1-sulfonamide 540.2468 104

N-[2-(2-fluorophenyl)ethyl]-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7- hexahydrocyclopenta[f]indazol-5-yl]methyl}octane-1-sulfonamide 596.3093 105

1-(2,4-dichlorophenyl)-N-[2-(2- fluorophenyl)ethyl]-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7- hexahydrocyclopenta[f]indazol-5-yl]methyl}methanesulfonamide 642.1514 106

1-(3-chlorophenyl)-N-[2-(2-fluorophenyl)ethyl]-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}methanesulfonamide 608.1905 107

1-(2-chlorophenyl)-N-[2-(2-fluorophenyl)ethyl]-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}methanesulfonamide 608.1908 108

N-[2-(2-fluorophenyl)ethyl]-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-1-[2-(trifluoromethyl)phenyl]methanesulfonamide 642.2171 109

N-(cyclopropylmethyl)-2,2,2-trifluoro-N-{1-[(4αR)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5- yl]ethyl}ethanesulfonamide512.6 110

N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(tetrahydrofuran-2-ylmethyl)-1-[3-(trifluoromethyl)phenyl]methanesulfonamide 604.7 111

1-(3,4-dichlorophenyl)-N-[2-(2- fluorophenyl)ethyl]-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7- hexahydrocyclopenta[f]indazol-5-yl]methyl}methanesulfonamide 642.1581 112

3-chloro-4-fluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-[(2S)-2-hydroxypropyl]benzenesulfonamide 548.1557 113

2,2,2-trifluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)- 4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-[(2S)-2-hydroxypropyl]benzenesulfonamide 502.1763 114

(1S)-2-{{[(4αR,5S)-1-(4-fluorophenyl)-4α- methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5- yl]methyl}[(2,2,2-trifluoroethyl)sulfonyl]amino}-1-methylethyl2,2,2-trifluoroethanesulfonate 648.1412 115

3-chloro-4-fluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-[(2R)-2-hydroxypropyl]benzenesulfonamide 548.1581 116

2-fluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α- methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-[2-(2-hydroxyphenyl)ethyl]benzenesulfonamide 576.2094 117

2-{[{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5- yl]methyl}(2-hydroxyethyl)amino]sulfonyl}benzamide 525.1951 118

2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5- yl]methyl}-N-(2-methoxyethyl)ethanesulfonamide 593 119

N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-[2-(2-methoxyphenyl)ethyl]-1-[3-(trifluoromethyl)phenyl]methanesulfonamide 654.2390 120

2,2,2-trifluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)- 4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-[2-(2-methoxyphenyl)ethyl]ethanesulfonamide 578.2097 121

2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-N-[2-(2-fluorophenyl)ethyl]-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7- hexahydrocyclopenta[f]indazol-5-yl]methyl}ethanesulfonamide 657.2340 122

N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-[2-(2-hydroxyphenyl)ethyl]-1-[3-(trifluoromethyl)phenyl]methanesulfonamide 640.2240 123

N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-[2-(2-hydroxyphenyl)ethyl]-3,5-dimethylisoxazole-4-sulfonamide 577.2259 124

N-[2-(2-fluorophenyl)ethyl]-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-1-pyridin-3-ylmethanesulfonamide 575.2262 125

N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-[2-(2-methoxyphenyl)ethyl]-1-pyridin-3-ylmethanesulfonamide 587.2464 126

2,2,2-trifluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)- 4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-[2-(3-methoxyphenyl)ethyl]ethanesulfonamide 578.2070 127

2,2,2-trifluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)- 4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-[2-(4-methoxyphenyl)ethyl]ethanesulfonamide 578.2079 128

2,2,2-trifluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)- 4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-pyridin-2-ylethyl)ethanesulfonamide 549.1918 129

2,2,2-trifluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)- 4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-pyridin-4-ylethyl)ethanesulfonamide 549.1914 130

2,2,2-trifluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)- 4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-[2-(4-hydroxyphenyl)ethyl]ethanesulfonamide 564.1927 131

N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-[2-(2-hydroxyphenyl)ethyl]-1-pyridin-3-ylmethanesulfonamide 573.2316 132

2,2,2-trifluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)- 4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(pyridazin-3-ylmethyl)ethanesulfonamide 536.1744 133

N-(3,3-difluoro-2-hydroxypropyl)-2,2,2-trifluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α- methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5- yl]methyl}ethanesulfonamide 538.1585134

2,2-difluoro-1-({{[(4αR,5S)-1-(4-fluorophenyl)- 4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5- yl]methyl}[(2,2,2-trifluoroethyl)sulfonyl]amino}methyl)ethyl2,2,2-trifluoroethanesulfonate 684.1219 135

2,2,2-trifluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)- 4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N- [(1-hydroxycyclopropyl)methyl]ethanesulfonamide 514.1782 136

1-({{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5- yl]methyl}[(2,2,2-trifluoroethyl)sulfonyl]amino}methyl)cyclopropyl2,2,2-trifluoroethanesulfonate 660.1408 137

2,2,2-trifluoro-N-[2-(2-fluorophenyl)ethyl]-N-{[(4αR,5S)-4α-methyl-1-phenyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5- yl]methyl}ethanesulfonamide 548.5 138

2,2,2-trifluoro-N-{[(4αR,5S)-4α-methyl-1- phenyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-pyridin-2-ylethyl)ethanesulfonamide 531.6 139

2,2,2-trifluoro-N-[2-(2-methoxyphenyl)ethyl]-N-{[(4αR,5S)-4α-methyl-1-phenyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5- yl]methyl}ethanesulfonamide 560.6 140

N-{[(4αR,5S)-4α-methyl-1-phenyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5- yl]methyl}-1-pyridin-3-yl-N-(2-pyridin-2- ylethyl)methanesulfonamide 539.6 141

N-[2-(2-hydroxyphenyl)ethyl]-N-{[(4αR,5S)-4α-methyl-1-phenyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-1-pyridin-3-ylmethanesulfonamide 555.7 142

2,2,2-trifluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)- 4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N- (2-hydroxy-2-pyridin-2-ylethyl)ethanesulfonamide 565.1900 143

2,2,2-trifluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)- 4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N- (2-hydroxy-2-pyridin-3-ylethyl)ethanesulfonamide 565.1889 144

2,2,2-trifluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)- 4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N- (2-hydroxy-2-pyridin-4-ylethyl)ethanesulfonamide 565.1891 145

2-{{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5- yl]methyl}[(2,2,2-trifluoroethyl)sulfonyl]amino}-1-pyridin-2- ylethyl2,2,2-trifluoroethanesulfonate 711.1517 146

2,2,2-trifluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)- 4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-pyridin-3-ylpropyl)ethanesulfonamide 563.2102 147

N-(3-amino-4,4,4-trifluorobutyl)-2,2,2-trifluoro-N-{[(4aR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}ethanesulfonamide 569.1797 148

N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(3,3,3-trifluoro-2- hydroxypropyl)propane-1-sulfonamide516.1924 149

N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-1-pyridin-3-yl-N-(3,3,3-trifluoro-2-hydroxypropyl)methanesulfonamide 565.1896 150

N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-1-methyl-N-(2-pyridin-2-ylethyl)-3-(trifluoromethyl)-1H-pyrazole-4-sulfonamide 615.2149 151

N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-pyridin-2-ylethyl)propane-1- sulfonamide 509.2363 152

2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5- yl]methyl}-N-(2-pyridin-2-ylethyl)ethanesulfonamide 640.2373 153

N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-pyridin-2-ylethyl)-1-[2-(trifluoromethyl)phenyl]methanesulfonamide 625.2239 154

N-(3,3-difluoro-2-hydroxypropyl)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-1-pyridin-3-ylmethanesulfonamide 547.1971 155

N-(3,3-difluoro-2-hydroxypropyl)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5- yl]methyl}propane-1-sulfonamide498.2020 156

N-(3,3-difluoro-2-hydroxypropyl)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4- sulfonamide 604.1808 157

N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-hydroxy-2-pyridin-2-ylethyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4- sulfonamide 631.2103 158

2-fluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α- methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-oxoethyl)benzenesulfonamide 498.1644 159

methyl 2-(2-{{[(4αR,5S)-1-(4-fluorophenyl)-4α- methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5- yl]methyl}[(2,2,2-trifluoroethyl)sulfonyl]amino}ethyl)benzoate 606.2037 160

methyl 5-chloro-2-(2-{{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7- hexahydrocyclopenta[f]indazol-5-yl]methyl}[(2,2,2- trifluoroethyl)sulfonyl]amino}ethyl)benzoate 640.1646161

N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-3,5-dimethylisoxazole-4-sulfonamide 457.1698 162

methyl 2-({[{[(4αR,5S)-1-(4-fluorophenyl)-4α- methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5- yl]methyl}(3,3,3-trifluoro-2-hydroxypropyl)amino]sulfonyl}methyl)benzoate 622.1984 163

2,2,2-trifluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)- 4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N- {2-[2-(hydroxymethyl)phenyl]ethyl}ethanesulfonamide 578.2086 164

2-({[{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}(3,3,3-trifluoro-2-hydroxypropyl)amino]sulfonyl}methyl)benzoic acid 608.1842 165

N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-1-pyridin-2-yl-N-(2-pyridin-2- ylethyl)methanesulfonamide558.2339 166

N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-1-pyridin-4-yl-N-(2-pyridin-2- ylethyl)methanesulfonamide558.2344 167

2-({[{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}(3,3,3-trifluoro-2- hydroxypropyl)amino]sulfonyl}methyl)benzamide 607.2606 168

N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-[(2R)-2-hydroxypropyl]-3,5- dimethylisoxazole-4-sulfonamide515.2157 169

N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-1-pyridin-3-ylmethanesulfonamide 453.1765 170

N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-3,5-dimethyl-N-(tetrahydrofuran-2-ylmethyl)isoxazole-4-sulfonamide 541.2284 171

N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5- yl]methyl}-N-(2-methoxyethyl)ethanesulfonamide 448.2 172

N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-methoxyethyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-sulfonamide 568.1987 173

N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-methoxyethyl)-3,5- dimethylisoxazole-4-sulfonamide515.1522 174

N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(tetrahydrofuran-2- ylmethyl)ethanesulfonamide 474.2237 175

N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-1-methyl-N-(tetrahydrofuran-2-ylmethyl)-3-(trifluoromethyl)-1H-pyrazole-4- sulfonamide 592.1982 176

N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N,3,5-trimethylisoxazole-4- sulfonamide 471.1882 177

2,2,2-trifluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)- 4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N- methylethanesulfonamide458.1537 178

N-ethyl-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α- methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-3,5-dimethylisoxazole-4-sulfonamide 485.2043 179

N-ethyl-2,2,2-trifluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7- hexahydrocyclopenta[f]indazol-5-yl]methyl}ethanesulfonamide 472.1697 180

methyl 2-[({{[(4αR,5S)-1-(4-fluorophenyl)-4α- methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5- yl]methyl}[(2R)-2-hydroxypropyl]amino}sulfonyl)methyl]benzoate e 568.2322 181

methyl 2-[({{[(4αR,5S)-1-(4-fluorophenyl)-4α- methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5- yl]methyl}[(2S)-2-hydroxypropyl]amino}sulfonyl)methyl]benzoate 568.2315 182

2-[({{[(4αR,5S)-1-(4-fluorophenyl)-4α- methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5- yl]methyl}[(2R)-2-hydroxypropyl]amino}sulfonyl)methyl]benzoic acid 554.2148 183

2-[({{[(4αR,5S)-1-(4-fluorophenyl)-4α- methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5- yl]methyl}[(2S)-2-hydroxypropyl]amino}sulfonyl)methyl]benzoic acid 554.2120 184

2-[({{[(4αR,5S)-1-(4-fluorophenyl)-4α- methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5- yl]methyl}[(2R)-2-hydroxypropyl]amino}sulfonyl)methyl]benzamide 553.2321 185

2-[({{[(4αR,5S)-1-(4-fluorophenyl)-4α- methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5- yl]methyl}[(2S)-2-hydroxypropyl]amino}sulfonyl)methyl]benzamide 553.2318 186

methyl 2-({{[(4αR,5S)-1-(4-fluorophenyl)-4α- methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5- yl]methyl}[(2R)-2-hydroxypropyl]amino}sulfonyl)benzoate 554.2168 187

methyl 2-({{[(4αR,5S)-1-(4-fluorophenyl)-4α- methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5- yl]methyl}[(2S)-2-hydroxypropyl]amino}sulfonyl)benzoate 554.2152 188

methyl 2-{[([2-(2- fluorophenyl)ethyl]{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7- hexahydrocyclopenta[f]indazol-5-yl]methyl}amino)sulfonyl]methyl}benzoate 632.2420 189

methyl 2-[([2-(2-fluorophenyl)ethyl]{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5- yl]methyl}amino)sulfonyl]benzoate618.2283 190

2-{[([2-(2-fluorophenyl)ethyl]{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7- hexahydrocyclopenta[f]indazol-5-yl]methyl}amino)sulfonyl]methyl}benzamide 617.2442 191

4-{[{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}(tetrahydrofuran-2- ylmethyl)amino]sulfonyl}benzamide 565.2192

3-[((2-fluorobenzyl){[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7- hexahydrocyclopenta[f]indazol-5-yl]methyl}amino)sulfonyl]benzamide 589.2 193

2,2,2-trifluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)- 4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(3-phenylpropyl)ethanesulfonamide 562.2124 194

N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-3,5-dimethyl-N-(3- phenylpropyl)isoxazole-4-sulfonamide575.247 195

2-fluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α- methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(3-phenylpropyl)benzenesulfonamide 574.2309 196

2-({[{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5- yl]methyl}(2-pyridin-2-ylethyl)amino]sulfonyl}methyl)benzamide 600.2476 197

N-{1-[(4αR)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]ethyl}-1-pyridin-3-yl-N-(2-pyridin-2- ylethyl)methanesulfonamide572.2 198

2-({[{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5- yl]methyl}(2-hydroxyethyl)amino]sulfonyl}methyl)benzamide 539.2 199

2-fluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α- methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-hydroxy-2-methylpropyl)benzenesulfonamide 528.6 200

2-fluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α- methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N- [(1-hydroxycyclopropyl)methyl]benzenesulfonamide 526.6 201

2-fluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α- methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N- [(1-hydroxycyclohexyl)methyl]benzenesulfonamide 568.6

For examples 93, 109 and 197, the following modification to the schemewas made:

Biological EvaluationBiological Evaluation (GR BIND)

The compounds exemplified in the present application exhibited activityin one or more of the following assays.

Ligand Binding Assay

-   Materials:-   Binding Buffer: TEGM (10 mM Tris-HCl, 1 mM EDTA, 10% glycerol, 1 mM    beta-mecaptoethanol, 10 mM Sodium Molybdate, pH 7.2)-   50% HAP Slurry: Calbiochem Hydroxylapatite, Fast Flow, in 10 mM    Tris, pH 8.0 and 1 mM EDTA.-   Wash Buffer: 40 mM Tris, pH7.5, 100 mM KCl, 1 mM EDTA and 1 mM EGTA.    95% EtOH-   Dexmethasone-methyl-³H, (DEX*); (Amersham cat# TRK645)-   Dexamethasone(DEX) (Sigma, cat# D1756):-   Hydroxylapatite Fast Flow; Calbiochem Cat#391947-   Molybdate=Molybdic Acid (Sigma, M1651)-   MDA-MB-453 cell culture media:

RPMI 1640 (Gibco 11835-055) w/23.8 mM NaHCO₃, 2 mM L-glutamine Finalconc. in 500 mL of complete media 10 mL (1M Hepes) 20 mM 5 mL (200 mML-glu)  4 mM 0.5 mL (10 mg/mL human insulin) 10 μg/mL in 0.01N HClCalbiochem#407694-S) 50 mL FBS (Sigma F2442) 10% 1 mL (10 mg/mLGentamicin 20 μg/mL Gibco#15710-072)Cell Passaging

Cells (Hall R. E., et al., European Journal of Cancer, 30A: 484-490(1994)) MDA-MB-453 (ATCC) cultured in RPMI 1640 (Gibco 11835-055)containing 20 mM Hepes, 4 mM L-glu, 10 ug/ml of human insulin (Sigma,I-0259), 10% FBS and 20 ug/ml of Gentamicin (Gibco#15710-072) are rinsedtwice in PBS. Phenol red-free Trypsin-EDTA is diluted in the samePBS1:10. The cell layers are rinsed with 1× Trypsin, extra Trypsin ispoured out, and the cell layers are incubated at 37° C. for ˜2 min. Theflask is tapped and checked for signs of cell detachment. Once the cellsbegin to slide off the flask, the complete media is added. The cells arecounted at this point, then diluted to the appropriate concentration andsplit into flasks or dishes for further culturing (Usually 1:3 to 1:6dilution).

Preparation of MDA-MB-453 Cell Lysate

When the cells are 70 to 85% confluent, they are detached as describedabove, and collected by centrifuging at 1000 g for 10 minutes at 4° C.The cell pellet is washed twice with TEGM (10 mM Tris-HCl, 1 mM EDTA,10% glycerol, 1 mM beta-mercaptoethanol, 10 mM Sodium Molybdate, pH7.2). After the final wash, the cells are resuspended in TEGM at aconcentration of 10⁷ cells/mL. The cell suspension is snap frozen inliquid nitrogen or ethanol/dry ice bath and transferred to −80° C.freezer on dry ice. Before setting up the binding assay, the frozensamples are left on ice-water to just thaw (˜1 hr). Then the samples arecentrifuged at 12,500 g to 20,000 g for 30 min at 4° C. The supernatantis used to set-up assay right away. If using 50 μL of supernatant, thetest compound can be prepared in 50 μL of the TEGM buffer.

Procedure for Multiple Compound Screening

1×TEGM buffer is prepared, and the isotope-containing assay mixture isprepared in the following order: EtOH (2% final concentration inreaction), 3H-DEX (Amersham Biosciences) and 1×TEGM. [e.g. For 100samples, 200 μL (100×2) of EtOH+4.25 μL of 1:10 ³H—Dex stock+2300 μL(100×23) 1×TEGM]. The compound is serially diluted, e.g., if startingfinal conc. is 1 μM, and the compound is in 25 μL of solution, forduplicate samples, 75 μL of 4×1 μM solution is made and 3 μL of 100 μMis added to 72 μL of buffer, and 1:5 serial dilution.

25 μL of ³H-DEX (6 nM) trace and 25 μL compound solution are first mixedtogether, followed by addition of 50 μL receptor solution. The reactionis gently mixed, spun briefly at about 200 rpm and incubated at 4° C.overnight. 100 μL of 50% HAP slurry is prepared and added to theincubated reaction which is then vortexed and incubated on ice for 5 to10 minutes. The reaction mixture is vortexed twice more to resuspend HAPwhile incubating reaction. The samples in 96-well format are then washedin wash buffer using The FilterMate™ Universal Harvester plate washer(Packard). The washing process transfers HAP pellet containingligand-bound expressed receptor to Unifilter-96 GF/B filter plate(Packard). The HAP pellet on the filter plate is incubated with 50 μL ofMICROSCINT (Packard) scintillint for 30 minutes before being counted onthe TopCount microscintillation counter (Packard). IC₅₄s are calculatedusing DEX as a reference.

Examples 1 to 201 were tested in the ligand binding assay anddemonstrated IC50s less than 1000 nM.

Trans-Activation Modulation of Glucocorticoid Receptor (GRAMMER)

This assay assesses the ability of test compounds to controltranscription from the MMTV-LUC reporter gene in lung adenocarcinomaA549 cells or MDA-MB-453 cells, a human breast cancer cell line thatnaturally expresses the human GR. The assay measures induction of amodified MMTV LTR/promoter linked to the LUC reporter gene.

The routine transient assay consists of plating 7,000-25,000 cells/wellof a white, clear-bottom 96-well plate. Alternatively, 384-well platescan be used at a cell concentration of 10,000/well. The media that thecells are plated in is “exponential growth medium” which consists ofphenol red-free RPMI1640 containing 10% FBS, 4 mM L-glutamine, 20 mMHEPES, 10 ug/mL human insulin, and 20 ug/mL gentamicin. Incubatorconditions are 37° C. and 5% CO₂. The transfection is done in batchmode. The cells are trypsinized and counted to the right cell number inthe proper amount of fresh media. It is then gently mixed with theFuGene6/DNA mix and plated onto the 96 or 384-well plate, all the wellsreceive 100 uL or 40 uL, respectively, of medium+lipid/DNA complex thenincubated 37° C. overnight. The transfection cocktail consists ofserum-free OptiMEM, FuGene6 reagent and DNA. The manufacturer's (RocheBiochemical) protocol for cocktail setup is as follows: The lipid to DNAratio is approximately 2.5:1 and the incubation time is 20 min at roomtemperature. Sixteen to 24 hours after transfection, the cells aretreated with dexamethasone to a final concentration of 10 nM as well asthe compound of interest, such that final DMSO (vehicle) concentrationis equal to or less than 1%. Each plate also contains samples that aretreated with 10 nM dexamethasone alone, which is used as the 100%activity control. The cells are exposed to the compounds for 24 hours.After 24 hours, the cells are lysed by a Promega cell culture lysisbuffer for approximately 30 min and then the luciferase activity in theextracts is assayed in the 96-well format luminometer. In 384-wellformat, Steady-Glo (Promega) or Steady-Lite (PerkinElmer) can be used byadding an equal volume of reagent to the media present in each well.Activity induced by 10 nM dexamethasone alone is set at 100% activity.Antagonist activity is calculated by determining the decrease indexamethasone-induced activity in response to compound treatmentrelative to samples that were treated with dexamethasone alone. Resultsare expressed as % inhibition of 10 nM dexamethasone activity or as foldof 10 nM dexamethasone activity. This transactivation assay can beperformed in an agonist and antagonist mode to identify these differentactivities.

Activity of test compounds is calculated as the E_(max) relative to theactivity obtained with 300 nM dexamethasone. Activity of test compoundsis calculated as the E_(max) relative to the activity obtained with 300nM DEX. The exemplified tissue selective glucocorticoid receptormodulators of the present invention display partial agonist activity inthis assay of greater than 5%.

The action of compounds is also tested in an antagonist mode(Anti-GRAMMER) in which the cells are treated with medium containing anagonist such as 10 nM DEX and the ability to agents to inhibit theactivation by an agonist is measured.

Transrepression Assay (GITAR)

This assay assesses the ability of test compounds to controltranscription from the TNFα-β-lactamase reporter gene in U937 cells, ahuman myelomonocytic leukemia cell line that naturally expresses thehuman GR. The assay measures compound dependent-repression of the TNFapromoter linked to a reporter gene.

The human U937 cells that had been stablely transfected with the TNF-αpromoter driving β-lactamase are used for this assay. U937 cells containan endogenous glucocorticoid receptor (GR). Cells are maintained in RPMI1640 Growth medium (Gibco Cat#11875-093) containing 25 mM HEPES, 10%FBS, 2 mM L-Glutamine, 1 mM Sodium pyruvate, 25 μg/ml Gentamicin (GibcoCat#15710-064), 1:1000 2-Mercaptoethanol (Gibco Cat#21985-023) and 0.8mg/ml G418 (Gibco Cat#10131-027). The density of the cells in the flaskneeds to be about 1×10⁶−3×10⁶/ml at the time of harvest. Usually, thecells are split to 1.2˜1.4×10⁵/ml (1:10) 3 days prior to the assay.50,000 cells/well are plated in 96 well black-walled plates the day ofassay. Test compounds are added 10 μL/well, and cells are incubated at37° C. for 30˜45 min. For assaying compounds, first dilute 1:10 in DMSOto make 1 mM, then further dilute 1:100 in medium to make 10× stockprior to adding to the cells. Add 50 ng/mlPMA (Sigma, cat# P8139) 10μL/well to a final concentration 5 ng/ml, and 1 μg/ml LPS (Sigma, cat#L4130) 10 μL/well to a final concentration 100 ng/ml. Incubate cells at37° C. overnight for ˜18 hr. PMA is stored frozen as 100 μg/ml stock inDMSO. Dilute 1:10 in DMSO for a working stock of 10 μg/ml and store at−20 C. For assaying, dilute the 10 μg/ml working stock 1:200 in mediumto make a 10× solution (50 ng/ml). Store frozen LPS at 1 mg/ml in PBS,dilute 1:1000 in medium to make 10× (1 μg/ml) for the assay. Add 6×loading buffer (CCF2-AM) 20 μL/well, and incubate at room temperaturefor 70˜90 min. Read plates on CytoFluor II Plate Reader according tomanufacture suggested protocols. The activity repressed by 100 nMdexamethasone alone is set as 100% activity.

Examples 1 to 201 were tested in the transrepression assay anddemonstrated maximal activity greater than 5%.

Microarray Analysis

All cell culture reagents were purchased from Invitrogen Life Tech,Carlsbad Calif. A549 cells were grown in phenol red-free DMEM/F12 mediumsupplemented with 10% FBS. Cells were grown at 37° C. with 5% CO₂. Usingthe RNeasy Kit (Qiagen Corp, Valencia Calif.), total RNA was extractedand purified from A549 cells treated with different GC compounds for 24hours, at a fully active dose. These cells express large amount of theGR and are very responsive to GC treatment. All samples were comparedagainst cells treated with vehicle. Expression levels of 23000 geneswere measured using oligonucleotide microarrays purchased from AgilentTechnologies, Inc. Each comparison was done on a pair of microarrayswith reversed fluorophores. Raw image intensity data were processedaccording to the method described in U.S. Pat. No. 6,351,712. The methodwas used to remove dye bias and to derive a Rosetta probability (p) andfold change value for each gene and each sample pair. Furthermore, foreach gene an ANOVA model was constructed across all treatments to deriveerror estimates. P values for evaluating expression differences werecomputed using a Bayesian adjusted t-test that was developed byLonnstedt and Speed (2002) and extended by Smyth (2003). A gene wasdeclared differentially expressed in any particular comparison if itsatisfied two critera:

1. The Rosetta p value had to be less than 0.1 and the Rosetta foldchange value had to be greater than 1.4 in at least one of thetreatments.

2. The ANOVA p value had to be less than 0.01 and the fold changegreater than 2 in the comparison under consideration.

In Vivo Inflammation Assay

Intact adult (6 month old) female Sprague-Dawley rats are used in theoxazolone (OX) contactdermatitis model. Rats were sensitized on theventral abdomen with OX on Day 0. On Days 7 and 9, a randomly-selectedear was challenged (same ear each time) with OX; the other was treatedwith vehicle. Daily treatment begun on Day 7 and continued for 7d withtest compounds at different doses and 1.3 mpk 6-methlyprednisolone or0.1 mpk DEX as positive controls. The thickness of both ears aremeasured on Days 11 and 14. Necropsy occurred on Day 14. The rat isfirst weighed, then anesthetized in a CO₂ chamber until near death.

Approximately 5 ml whole blood is obtained by cardiac puncture. The ratis then examined for certain signs of death and completeness. Tissuesare dissected in a highly stylized fashion. The following endpoints wereevaluated: a) inhibiting ear inflammation induced by oxazalone, b)raising serum insulin, c) reducing serum ACTH, d) reducing spleenweight, e) reducing skin thickness, f) reducing body weight, g)increasing expression of bone-related genes with potential relationshipto negative glucocorticoid effects on bone; e) changes in molecularmarkers that correlate with skin inflammation, skin thinning, muscleatrophy and glucose metabolism in liver. All blood samples werecollected between 1330-1530 hours, ˜4-5 hrs after the last compoundtreatment.

Primary data for this assay are left and right ear thickness. Inter-earthickness difference (etd) is used for the estimating the level ofinflammation and effectiveness of the compounds is determined by theirability to reduce the increase the thickness of the inflamed ear. Backof the rat skin thickness, spleen weight, serum insulin as well as theeffects of gcs on the expression of molecular markers in skininflammation, skin atrophy, muscle atrophy and glucose metabolism inliver are measured. Data are analyzed by anova plus fisher plsd post-hoctest to identify intergroup differences.

Transactivation Transrepression GR A549 Cells U937 Cells BIND GRAMMERGITAR GITAR > Compound Ki IP Emax IP Emax GRAMM number (nM) (nM) (%)(nM) (%) % SEP 1 1.8 350.7 31.6 406.8 73.5 41.9 2 0.6 218.1 50.5 259.873.3 22.7 3 0.8 368.2 39.3 406.6 65.1 25.8 4 2.2 293.8 16.9 256.0 53.136.2 5 1.0 421.5 2.9 222.8 19.2 16.2 6 0.9 402.4 13.0 1010.0 49.0 36.0 70.4 351.4 36.3 388.8 56.0 19.7 8 1.9 37.0 4.9 424.0 17.4 12.4 9 2.21131.0 12.7 959.5 28.1 15.4 10 0.7 614.8 12.3 464.7 46.6 34.4 11 0.7235.0 66.0 205.8 89.1 23.1 12 1.8 331.4 34.4 279.8 64.2 29.8 13 0.6 82.98.3 305.4 16.1 7.8 14 1.6 344.3 25.2 553.5 59.3 34.1 15 1.8 291.7 27.6257.9 59.0 31.4 16 3.0 254.5 53.0 268.5 84.5 31.4 17 2.1 219.7 37.3347.5 82.1 44.8 18 0.8 394.2 20.0 415.2 35.3 15.3 19 4.0 1187.0 20.61721.0 69.8 49.1 20 2.2 909.5 68.1 372.7 69.7 1.6 21 3.0 518.8 33.5365.5 58.7 25.2 22 3.5 453.2 27.9 395.0 71.8 43.9 23 4.9 8787.0 2.72253.0 34.0 31.3 24 5.3 845.1 10.5 564.6 37.7 27.2 25 2.5 453.0 76.4222.5 89.4 13.0 26 9.7 939.0 5.8 25.0 16.0 10.2 27 8.8 994.3 3.0 637.513.0 10.0 28 2.3 483.2 44.0 662.3 78.8 34.8 29 8.4 1712.0 4.7 838.4 30.926.2 30 7.6 1638.0 3.5 416.9 19.9 16.4 31 6.1 833.5 20.7 678.7 54.8 34.032 3.9 867.6 29.4 555.4 63.1 33.7 33 8.8 1051.0 15.2 1205.0 59.7 44.5 341.7 748.2 37.0 1775.0 45.9 8.9 35 5.1 443.3 4.9 777.4 39.5 34.6 36 2.5744.5 22.7 540.0 72.2 49.5 37 10.7 2189.0 2.8 1354.0 33.8 30.9 38 6.45000.0 1.3 2340.0 33.8 32.5 39 8.1 5000.0 1.7 34.9 17.1 15.5 40 10.582.8 3.2 35.5 19.8 16.6 41 5.9 124.3 60.3 361.5 91.9 31.6 42 5.9 228.14.2 391.3 19.2 15.1 43 2.2 469.7 36.0 1099.0 71.8 35.8 44 1.6 621.8 44.81055.0 65.6 20.8 45 2.4 2887.0 11.4 1391.0 12.8 1.3 46 0.7 372.6 83.3187.5 85.5 2.1 47 0.7 635.4 58.3 894.9 74.0 15.7 48 0.9 995.0 8.8 175.324.5 15.7 49 1.8 955.4 14.1 922.2 23.0 8.9 50 6.5 948.6 15.1 959.5 61.346.2 51 2.5 433.1 83.3 185.8 86.8 3.5 52 1.9 569.7 31.9 868.8 54.4 22.553 3.7 865.9 18.1 832.3 54.0 36.0 54 8.5 1080.0 8.2 1101.0 31.3 23.1 552.7 549.5 47.7 337.0 83.4 35.7 56 4.6 804.9 50.9 642.7 86.9 36.1 57 3.4864.7 2.7 1200.0 23.8 21.0 58 2.3 1077.0 3.1 736.9 28.8 25.7 59 2.6437.0 41.3 537.8 80.9 39.6 60 4.4 776.9 23.0 813.5 52.0 29.0 61 2.5417.3 5.8 1554.0 31.3 25.5 62 3.5 404.3 26.0 855.6 68.5 42.5 63 9.11408.0 2.1 404.2 12.0 9.9 64 3.0 621.5 7.9 731.0 29.0 21.1 65 2.7 1085.019.6 894.2 61.0 41.3 66 7.9 1176.0 5.3 929.3 24.5 19.2 67 13.4 450.0 6.52063.0 29.3 22.8 68 3.6 950.6 10.0 757.0 32.9 22.9 69 8.7 852.2 12.62536.0 34.8 22.2 70 4.5 564.0 25.8 1008.0 40.8 15.1 71 5.0 256.9 63.1302.3 82.3 19.2 72 1.4 474.5 35.3 486.5 60.8 25.5 73 3.1 363.9 25.4363.5 81.4 56.0 74 3.0 1026.0 34.1 1144.0 44.1 9.9 75 2.5 450.4 14.4473.2 28.8 14.4 76 7.7 1963.0 3.5 2110.0 13.0 9.5 77 1.8 901.0 17.91126.0 43.6 25.7 78 2.3 652.2 50.6 882.7 66.5 15.9 79 4.8 1318.0 7.51947.0 71.8 64.3 80 13.7 1141.0 6.0 2584.0 70.0 64.0 81 7.2 460.6 17.2959.3 76.7 59.5 82 3.2 287.4 61.1 220.2 90.2 29.1 83 3.7 567.8 6.91317.0 59.5 52.6 84 2.6 441.9 19.7 799.2 86.0 66.3 85 6.9 73.7 1.64235.0 38.8 37.1 86 4.2 68.6 68.2 262.4 80.6 12.4 87 2.8 231.3 65.1212.1 85.1 20.0 88 3.7 617.6 25.3 645.8 57.7 32.4 89 2.4 119.3 81.4137.5 95.6 14.3 90 3.6 353.9 33.5 651.2 67.6 34.0 91 2.0 642.9 10.7973.1 61.5 50.8 92 3.0 504.4 41.6 493.2 68.5 26.9 93 2.7 295.7 50.9231.2 71.8 20.8 94 2.9 422.8 43.9 412.4 75.5 31.6 95 5.2 559.5 70.4464.1 73.1 2.7 96 1.1 152.4 65.7 124.2 85.0 19.3 97 0.3 48.9 83.8 49.085.9 2.2 98 1.5 239.5 76.7 64.3 89.9 13.2 99 1.4 235.7 62.1 64.4 86.824.6 100 2.1 397.2 64.9 191.6 79.1 14.2 101 3.4 181.7 62.8 61.1 95.432.6 102 2.6 202.9 78.3 95.1 86.5 8.2 103 1.7 366.8 68.8 177.2 76.5 7.7104 9.8 257.7 9.2 153.3 10.2 1.0 105 1.7 192.6 85.5 109.2 88.8 3.3 1061.7 327.6 82.8 44.1 85.3 2.5 107 1.8 395.0 73.0 54.1 84.4 11.4 108 2.3520.7 46.0 184.7 70.5 24.6 109 2.1 208.6 54.1 189.8 91.1 37.0 110 1.41101.0 4.9 625.9 26.2 21.3 111 1.8 747.7 37.6 325.3 75.7 38.1 112 1.7423.3 33.4 337.4 65.7 32.3 113 2.2 54.7 85.4 59.0 94.0 8.7 114 0.8 161.080.3 147.6 98.5 18.2 115 2.9 786.3 26.1 642.8 57.4 31.2 116 1.4 676.373.5 94.9 81.2 7.7 117 9.4 448.9 45.1 533.3 73.7 28.6 118 3.8 853.1 8.71050.0 34.1 25.4 119 2.3 202.3 6.6 605.0 15.9 9.3 120 1.3 109.5 73.277.8 91.5 18.2 121 5.3 241.6 15.9 156.5 33.8 17.9 122 2.9 502.4 8.9417.4 39.7 30.8 123 0.9 194.6 65.4 127.6 90.8 25.4 124 0.7 217.7 99.2250.5 100.5 1.3 125 1.0 508.0 21.2 574.9 55.3 34.1 126 0.9 227.3 78.2232.9 90.0 11.7 127 1.1 231.9 67.9 202.1 83.0 15.1 128 0.8 251.7 69.1324.5 88.4 19.3 129 1.9 948.4 67.2 622.8 79.1 11.9 130 1.8 369.3 66.1229.4 79.7 13.6 131 1.7 570.6 37.4 437.0 60.3 22.9 132 5.5 421.5 23.2791.2 74.0 50.8 133 0.8 67.5 73.4 82.6 95.9 22.5 134 1.8 216.1 89.2243.4 93.8 4.7 135 2.9 126.9 68.8 258.0 87.9 19.2 136 2.5 278.7 58.8440.9 100.8 42.0 137 0.9 142.6 73.6 324.0 87.6 14.0 138 1.2 203.5 78.1433.3 83.7 5.6 139 1.5 262.3 70.7 798.3 72.4 1.7 140 4.1 704.3 21.31573.0 37.0 15.6 141 1.1 441.3 22.6 399.7 62.2 39.7 142 0.9 122.8 78.1140.2 92.5 14.4 143 13.3 252.2 83.5 225.1 91.2 7.7 144 0.9 397.4 73.6334.1 91.6 18.1 145 1.0 203.9 60.2 196.1 93.5 33.3 146 0.8 263.0 91.5308.0 93.3 1.8 147 3.2 475.5 78.1 707.6 78.4 0.3 148 1.6 402.5 62.6858.3 77.6 14.9 149 1.8 351.0 32.4 249.7 77.1 44.7 150 1.5 346.0 45.6376.1 79.3 33.7 151 1.3 421.2 76.0 551.1 83.3 7.2 152 1.6 63.9 2.01026.0 23.0 21.0 153 1.2 315.2 15.2 262.5 52.4 37.2 154 1.3 509.2 17.9616.3 66.5 48.7 155 2.9 988.8 29.0 1094.0 61.3 32.2 156 2.5 193.4 4.5228.5 19.5 15.0 157 0.8 124.0 63.6 29.1 93.6 30.0 158 4.2 746.9 36.2564.2 77.8 41.6 159 1.9 366.8 28.9 551.5 34.1 5.2 160 3.4 546.8 4.3508.3 15.1 10.8 161 4.8 418.8 18.3 930.3 45.0 26.7 162 0.5 322.5 87.1202.4 90.8 3.7 163 1.7 241.2 48.4 341.8 86.9 38.6 164 3.2 1076.0 58.31252.0 81.3 23.0 165 1.6 306.2 37.8 286.3 61.1 23.4 166 1.6 302.6 56.4548.7 71.7 15.3 167 2.2 149.9 74.9 159.4 87.4 12.5 168 1.5 123.0 48.1118.7 83.1 35.0 169 20.9 1663.0 12.4 3027.0 68.5 56.1 170 2.6 431.7 76.0759.0 87.7 11.8 171 7.0 287.4 71.3 409.7 88.0 16.7 172 0.6 398.5 10.7718.0 42.4 31.8 173 1.3 364.1 70.4 520.4 83.0 12.6 174 3.4 527.1 81.1423.4 85.3 4.2 175 1.0 381.3 22.7 822.2 47.5 24.8 176 1.3 246.3 56.9316.1 74.5 17.6 177 1.6 168.6 67.3 176.6 80.2 12.9 178 1.2 109.9 55.0275.6 74.5 19.5 179 1.2 277.2 65.4 440.2 96.5 31.2 180 1.8 246.9 38.1186.8 77.7 39.5 181 2.8 363.7 54.6 262.6 79.2 24.7 182 93.9 4764.0 8.01895.0 16.2 8.2 183 64.0 4498.0 15.0 3311.0 23.2 8.2 184 9.6 421.5 21.6562.4 60.3 38.7 185 13.1 249.6 19.9 675.7 63.0 43.1 186 1.9 509.3 35.8697.1 63.5 27.7 187 2.5 356.7 35.8 391.7 71.5 35.6 188 1.2 236.2 30.4190.2 60.5 30.1 189 1.1 151.5 65.3 189.2 81.0 15.7 190 1.5 424.3 65.1387.8 77.4 12.4 191 2.0 338.0 27.1 440.5 37.2 10.1 192 0.9 170.4 4.32907.0 27.5 23.2 193 1.0 303.4 55.4 170.4 74.0 18.6 194 1.5 516.8 41.9291.0 56.2 14.4 195 0.6 542.2 12.9 485.8 30.0 17.1 196 2.7 552.3 36.6386.8 40.3 3.7 197 4.4 769.0 43.7 1040.0 45.5 1.8 198 14.3 1227.0 8.21148.0 15.5 7.3 199 2.4 96.8 58.6 506.5 80.8 22.2 200 1.8 47.9 57.5307.7 85.9 28.4 201 2.3 88.4 47.8 485.6 69.5 21.7

The compounds shown in the Table immediately above were tested in thebinding, GRAMMER and GITAR assays and demonstrated a superior activityprofile. The compounds shown in Table I have potencies in the GRAMMERand GITAR assays (as measured by inflection points, IP) of less than6000 nM concomitant with maximum activity in the GRAMMER assay less thanthe maximum activity in the GITAR assay.

Preferred compounds have potencies in the GRAMMER and GITAR assay (asmeasured by the inflection points, IP) of less than 300 nM concomitantwith a maximum activity in the activity in the GRAMMER assay of lessthan 60% and a maximum activity in the GITAR assay of between 40 and80%.

1. A compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein R¹ is selectedfrom the group consisting of: (a) C₁₋₆alkyl, optionally mono-, di- ortri substituted with substituents independently selected from (1) halo,(2) —CF₃, (3) hydroxyl, (4) oxo, (5) —CN, and (6) pyridine, (b)C₂₋₆alkenyl, optionally mono-, di- or tri substituted with fluoro, (c)—C₃₋₆cycloalkyl, (d) —C₁₋₂alkylC₃₋₆cycloalkyl, (e) heterocycle, (f)—C₁₋₂alkylheterocycle, (g) aryl selected from phenyl or naphthyl, (h)—C₁₋₂alkylaryl, (i) —C₂₋₄alkenylaryl, (j) heteroaryl, (k)—C₁₋₂alkylheteroaryl, (l) —Oheteroaryl, (m) —OC₁₋₆alkyl optionallymono-, di- or tri substituted with fluoro, (n) —C1-4alkyl-O—C1-6alkyl,optionally substituted with hydroxy, or —O—S(O)₂—C₁₋₂alkyl-CF₃, (o)—OC₃₋₆cycloalkyl, and (p) —Oaryl, wherein the heteroaryl, aryl andheterocycle of choices (e), (f), (g), (h), (i), (j), (k), (l), and (p)are optionally substituted with 1, 2 or 3 substituents independentlyselected from the group consisting of (1) hydroxyl, (2) halo, (3) —CN,(4) —CF₃, (5) —C₁₋₄alkyl, (6) —OC₁₋₄alkyl, (7) —O—CH₂CF₃, (8) heteroarylselected from pyrazole, thiophene, imidazole, and oxazole, optionallysubstituted with 1, 2 or 3 substitutents independently selected frommethyl CF₃ and halo, (9) —NH—OCH₃, (10) phenyl, (11) —O-phenyl, (12)pyridine, (13) —O-pyridine, (14) —NH—C(O)—NH—CH₃, (15)—NH—C(O)—C₁₋₄alkyl, (16) —NH—C(O)—C₃₋₆cycloalkyl, (17)—C₁₋₃alkyl-C(O)—OH, (18) —C₁₋₃alkyl-C(O)—O—CH₃, (19) —C(O)—NH₂, (20)—C(O)—C₁₋₄alkyl-NH₂, (21) —C(O)—NH—C₃₋₆cycloalkyl, (22) —C(O)—OH, (23)—C(O)—O—C₁₋₄alkyl, (24) —C₁₋₂alkyl-heterocycle, (25)—C₂₋₄alkenyl-C(O)-phenyl, and (26) —O—S(O)₂—C₁₋₂alkyl-CF₃; R² isselected from the group consisting of: (a) H, (b) OH, (c) C₁₋₈alkyl,optionally mono-, di- or tri substituted with substituents independentlyselected from (1) halo, (2) hydroxyl, (3) oxo, (4) —CN, (5) CHF2, (6)CF3, (7) pyridyl, (8) —O—S(O)₂—CF₃, and (9) —O—S(O)₂—C₁₋₂alkyl-CF₃, (d)C₂₋₆alkenyl, optionally mono-, di- or tri substituted with fluoro, (e)—C₁₋₂alkylC₃₋₆cycloalkyl, (f) heterocycle, (g) —C₁₋₂alkylheterocycle,(h) aryl selected from phenyl or naphthyl, (i) —C₁₋₃alkylaryl, (j)—C₂₋₄alkenylaryl, (k) heteroaryl, (l) —C₁₋₂alkylheteroaryl, (m)—CH₂pyridyl, and (o) —C₁₋₄alkyl-O—C₁₋₆alkyl, optionally substituted withhydroxy, or —O—S(O)₂—C₁₋₂alkyl-CF₃, wherein the cycloalkyl, heteroaryl,aryl and heterocycle of choices (e), (f), (g), (h), (i), (j), (k), (l)and (m) are optionally substituted with 1, 2 or 3 substituentsindependently selected from the group consisting of (1) hydroxyl, (2)halo, (3) —CN, (4) —CF₃, (5) —C₁₋₄alkyl, (6) —OCH₃, (7) —O—CH₂CF₃, (8)heteroaryl selected from pyrazole, thiophene, imidazole, and oxazole,optionally substituted with 1, 2 or 3 substitutents independentlyselected from methyl, and halo, (9) —NH—OCH₃, (10) phenyl, (11)—O-phenyl, (12) pyridine, (13) —O-pyridine, (14) —NH—C(O)—NH—CH₃, (15)—NH—C(O)—C₁₋₄alkyl, (16) —NH—C(O)—C₃₋₆cycloalkyl, (17)—C₁₋₃alkyl-C(O)—OH, (18) —C₁₋₃alkyl-C(O)—O—CH₃, (19) —C(O)—NH₂, (20)—C(O)—C₁₋₄alkyl-NH₂, (21) —C(O)—NH—C₃₋₆cycloalkyl, (22) —C(O)—OH, (23)—C(O)—O—C₁₋₄alkyl, (24) —C₁₋₂alkyl-heterocycle, (25)—C₂₋₄alkenyl-C(O)-phenyl, and (26) —O—S(O)₂—C₁₋₂alkyl-CF₃; R³ isselected from (a) H, (b) C₁₋₆alkyl, (c) C₃₋₆cycloalkyl, and (d)C₁₋₆fluoroalkyl; and R⁴ is hydrogen or F.
 2. The compound according toclaim 1 wherein R¹ is selected from the group consisting of: (a)C₁₋₆alkyl, optionally mono-, di- or tri substituted with substituentsindependently selected from (1) halo selected from fluoro and chloro,(2) —CF₃, (3) hydroxyl, and (4) pyridine, (b) C₂₋₆alkenyl, optionallymono-, di- or tri substituted with fluoro, (c) —C₃₋₆cycloalkyl, (d)—C₁₋₂alkylC₃₋₆cycloalkyl, (e) heterocycle, (f) —C₁₋₂alkylheterocycle,(g) aryl selected from phenyl or naphthyl, (h) —C₁₋₂alkylaryl, (i)—C₂₋₄alkenylaryl, (j) heteroaryl, (k) —C₁₋₂alkylheteroaryl, (l)—Oheteroaryl, (m) —OC₁₋₆alkyl optionally mono-, di- or tri substitutedwith fluoro, (n) —C1-4alkyl-O—C1-6alkyl, optionally substituted withhydroxy, or —O—S(O)₂—C₁₋₂alkyl-CF₃, (O) —OC₃₋₆cycloalkyl, and (p)—Oatyl, wherein the heteroaryl, aryl and heterocycle of choices (e),(f), (g), (h), (i), (j), (k), (l), and (p) are optionally substitutedwith 1, 2 or 3 substituents independently selected from the groupconsisting of (1) hydroxyl, (2) halo, (3) —CN, (4) —CF₃, (5) —C₁₋₄alkyl,(6) —OC₁₋₄alkyl. (7) —O—CH₂CF₃, (8) —NH—OCH₃, (9) —NH—C(O)—NH—CH₃, (10)—NH—C(O)—C₁₋₄alkyl, (11) —NH—C(O)—C₃₋₆cycloalkyl, (12)—C₁₋₃alkyl-C(O)—OH, (13) —C₁₋₃alkyl-C(O)—O—Ch₃, (14) —C(O)—NH₂, (15)—C(O)—C₁₋₄alkyl-NH₂, (16) —C(O)—NH—C₃₋₆cycloalkyl, (17) —C(O)—OH, (18)—C(O)—O—C₁₋₄alkyl, (19) —C₁₋₂alkyl-heterocycle, (20)—C₂₋₄alkenyl-C(O)-phenyl, and (21) —O—S(O)₂—C₁₋₂alkyl-CF₃.
 3. Thecompound according to claim 2 wherein R¹ is selected from the groupconsisting of: (a) C₁₋₆alkyl, optionally mono-, di- or tri substitutedwith substituents independently selected from (1) halo selected fromfluoro and chloro, (2) —CF₃, (3) hydroxyl, and (4) pyridine, (b)—C₃₋₆cycloalkyl, (c) —C₁₋₂alkylC₃₋₆cycloalkyl, (d) heterocycle, (e)—C₁₋₂alkylheterocycle, (f) aryl selected from phenyl or naphthyl, (g)—C₁₋₂alkylaryl, (h) heteroaryl, (i) —C₁₋₂alkylheteroaryl, wherein theheteroaryl, aryl and heterocycle of choices (d), (e), (f), (g), (h) and(i) are optionally substituted with 1, 2 or 3 substituents independentlyselected from the group consisting of (1) halo, (2) —CN, (3) —CF₃, (4)—C₁₋₄alkyl, (5) —OC₁₋₄alkyl, (6) —O—CH₂CF₃, (7) —C(O)—NH₂, and (8)—C(O)—O—C₁₋₄alkyl.
 4. The compound according to claim 3 wherein R¹ isselected from the group consisting of: (a) C₁₋₆alkyl, optionally mono-,di- or tri substituted with substituents independently selected from (1)halo selected from fluoro and chloro, (2) —CF₃, (3) hydroxyl, and (4)pyridine, (b) aryl selected from phenyl or naphthyl, (c) —C₁₋₂alkylaryl,(d) heteroaryl, and (e) —C₁₋₂alkylheteroaryl, wherein the heteroaryl,aryl and heterocycle of choices (b), (c), (d) and (e) are optionallysubstituted with 1, 2 or 3 substituents independently selected from thegroup consisting of (1) halo, selected from fluoro and chloro (2) —CF₃,(3) —C₁₋₄alkyl, (4) —OC₁₋₄alkyl, (5) —C(O)—NH₂, and (6)—C(O)—O—C₁₋₄alkyl.
 5. The compound according to claim 1 wherein R² isselected from the group consisting of: (a) H, (b) OH, (c) C₁₋₈alkyl,optionally mono-, di- or tri substituted with substituents independentlyselected from (1) halo, (2) hydroxyl, (3) oxo, (4) —CN, (5) CHF₂, (6)CF₃, (7) pyridyl, and (8) —O—S(O)₂—C₁₋₂alkyl-CF₃; (d) C₂₋₆alkenyl,optionally mono-, di- or tri substituted with fluoro, (e)—C₁₋₂alkylC₃₋₆cycloalkyl, (f) heterocycle, (g) —C₁₋₂alkylheterocycle,(h) aryl selected from phenyl or naphthyl, (i) —C₁₋₂alkylaryl, (j)—C₂₋₄alkenylaryl, (k) heteroaryl, (l) —C₁₋₂alkylheteroaryl, (m)—CH₂pyridyl, (O) —C1-4alkyl-O—C1-6alkyl, optionally substituted withhydroxy, or —O—S(O)₂—C₁₋₂alkyl-CF₃, wherein the cycloalkyl, heteroaryl,aryl and heterocycle of choices (e), (f), (g), (h), (i), (j), (k), (l)and (m) are optionally substituted with 1, 2 or 3 substituentsindependently selected from the group consisting of (1) hydroxyl, (2)halo, (3) —CN, (4) —CF₃, (5) —C₁₋₄alkyl, (6) —OCH₃, (7) —O—CH₂CF₃, (8)—NH—C(O)—NH—CH₃, (9) —NH—C(O)—C₁₋₄alkyl, (10) —NH—C(O)—C₃₋₆cycloalkyl,(11) —C₁₋₃ alkyl-C(O)—OH, (12) —C₁₋₃alkyl-C(O)—O—CH₃, (13) —C(O)—NH₂,(14) —C(O)—C₁₋₄alkyl-NH₂, (15) —C(O)—NH—C₃₋₆cycloalkyl, (16) —C(O)—OH,(17) —C(O)—O—C₁₋₄alkyl, (18) —C₁₋₂alkyl-heterocycle, (19)—C₂₋₄alkenyl-C(O)-phenyl, and (20) —O—S(O)₂—C₁₋₂alkyl-CF₃.
 6. Thecompound according to claim 5 wherein R² is selected from the groupconsisting of (a) H, (b) OH, (c) C₁₋₈alkyl, optionally mono-, di- or trisubstituted with substituents independently selected from (1) halo, (2)hydroxyl, (3) oxo, (4) —CN, (5) CHF₂, (6) CF₃, and (7)—O—S(O)₂—C₁₋₂alkyl-CF₃; (d) —C₁₋₂alkylC₃₋₆cycloalkyl, (e)—C₁₋₂alkylheterocycle, (f) aryl selected from phenyl or naphthyl, (g)—C₁₋₂alkylaryl, (h) heteroaryl, (i) —C₁₋₂alkylheteroaryl, (j)—C₁₋₄alkyl-O—CH₃, wherein the cycloalkyl, heteroaryl, aryl andheterocycle of choices (d), (e), (f), (g), (h) and (i) are optionallysubstituted with 1, 2 or 3 substituents independently selected from thegroup consisting of (1) hydroxyl, (2) halo, (3) —CN, (4) —CF₃, (5)—C₁₋₄alkyl, (6) —OCH₃, (7) —O—CH₂CF₃, (8) —NH—C(O)—NH—CH₃, (9)—NH—C(O)—C₁₋₄alkyl, (10) —NH—C(O)—C₃₋₆cycloalkyl, (11)—C₁₋₃alkyl-C(O)—OH, (12) —C₁₋₃alkyl-C(O)—O—CH₃, (13) —C(O)—NH₂, (14)—C(O)—C₁₋₄alkyl-NH₂, (15) —C(O)—NH—C₃₋₆cycloalkyl, (16) —C(O)—OH, (17)—C(O)—O—C₁₋₄alkyl, (18) —C₁₋₂alkyl-heterocycle, (19)—C₂₋₄alkenyl-C(O)-phenyl, and (20) —O—S(O)₂—C₁₋₂alkyl-CF₃.
 7. Thecompound according to claim 6 wherein R² is selected from the groupconsisting of: (a) H, (b) OH, (c) C₁₋₈alkyl, optionally mono-, di- ortri substituted with substituents independently selected from (1) halo,(2) hydroxyl, (3) CHF₂, (4) CF₃, and (5) —O—S(O)₂—C₁₋₂alkyl-CF₃; (d)—C₁₋₂alkylC₃₋₆cycloalkyl, (e) aryl selected from phenyl or naphthyl, (f)—C₁₋₂alkylaryl, (g) —C₁₋₂alkylheteroaryl, (h) —C₁₋₄alkyl-O—CH₃, whereinthe cycloalkyl, heteroaryl, aryl and heterocycle of choices (d), (e),(f), (g), (h) and (i) are optionally substituted with 1, 2 or 3substituents independently selected from the group consisting of (1)hydroxyl, (2) halo, (3) —CN, (4) —CF₃, (5) —C₁₋₄alkyl, (6) —OCH₃, (7)—O—CH₂CF₃, and (8) —O—S(O)₂—C₁₋₂alkyl-CF₃.
 8. The compound according toclaim 1 wherein R³ is selected from (a) H, and (b) C₁₋₆alkyl.
 9. Thecompound according to claim 8 wherein R³ is hydrogen.
 10. The compoundaccording to claim 1 wherein: R⁴ is F.
 11. The compound of claim 1 ofFormula II

or a pharmaceutically acceptable salt thereof wherein R¹ is selectedfrom the group consisting of: (a) C₁₋₆alkyl, optionally mono-, di- ortri substituted with substituents independently selected from (1) haloselected from fluoro and chloro, (2) —CF₃, (3) hydroxyl, and (4)pyridine, (b) aryl selected from phenyl or naphthyl, (c) —C₁₋₂alkylaryl,(d) heteroaryl, (e) —C₁₋₂alkylheteroaryl, wherein the heteroaryl, aryland heterocycle of choices (b), (c), (d) and (e) are optionallysubstituted with 1, 2 or 3 substituents independently selected from thegroup consisting of (1) halo, selected from Fluoro and Chloro (2) —CF₃,(3) —C₁₋₄alkyl, (4) —OC₁₋₄-alkyl, (5) —C(O)—NH₂, and (6)—C(O)—O—C₁₋₄alkyl; and R² is selected from the group consisting of: (a)H, (b) OH, (c) C₁₋₈alkyl, optionally mono-, di- or tri substituted withsubstituents independently selected from (1) halo, (2) hydroxyl, (3)CHF₂, (4) CF₃, and (5) —O—S(O)₂—C₁₋₂alkyl-CF₃; (d)—C₁₋₂alkylC₃₋₆cycloalkyl, (e) aryl selected from phenyl or naphthyl, (f)—C₁₋₂alkylaryl, (g) —C₁₋₂alkylheteroaryl, (h) —C₁₋₄alkyl-O—CH₃, whereinthe cycloalkyl, heteroaryl, aryl and heterocycle of choices (d), (e),(f), (g), (h) and (i) are optionally substituted with 1, 2 or 3substituents independently selected from the group consisting of (1)hydroxyl, (2) halo, (3) —CN, (4) —CF₃, (5) —C₁₋₄alkyl, and (6) —OCH₃.12. The compound according to claim 11 wherein R¹ is selected from thegroup consisting of: (a) C₁₋₆alkyl, optionally mono-, di- or trisubstituted with substituents independently selected from (1) haloselected from fluoro and chloro, (2) —CF₃, (3) hydroxyl, and (4)pyridine, (b) aryl selected from phenyl or naphthyl, (c) —C₁₋₂alkylaryl,(d) heteroaryl, and (e) —C₁₋₂alkylheteroaryl, wherein the heteroaryl,aryl and heterocycle of choices (b), (c), (d) and (e) are optionallysubstituted with 1, 2 or 3 substituents independently selected from thegroup consisting of (1) halo, selected from fluoro and chloro (2) —CF₃,(3) —C₁₋₄alkyl, (4) —OC₁₋₄alkyl, (5) —C(O)—NH₂, and (6)—C(O)—O—C₁₋₄alkyl; and R² is selected from the group consisting of: (a)H, (b) OH, (c) C₁₋₈alkyl, optionally mono-, di- or tri substituted withsubstituents independently selected from (1) halo, (2) hydroxyl, (3)CHF₂, (4) CF₃, and (5) —O—S(O)₂—C₁₋₂alkyl-CF₃, (d)—C₁₋₂alkylC₃₋₆cycloalkyl, (e) aryl selected from phenyl or naphthyl, (f)—C₁₋₂alkylaryl, (g) —C₁₋₂alkylheteroaryl, (h) —C₁₋₄alkyl-O—CH₃, whereinthe cycloalkyl, heteroaryl, aryl and heterocycle of choices (d), (e),(f), (g), (h) and (i) are optionally substituted with 1, 2 or 3substituents independently selected from the group consisting of (1)halo, (2) —CF₃, (3) —C₁₋₄alkyl, and (4) —OCH₃, or a pharmaceuticallyacceptable salt thereof.
 13. A compound selected fromN-{[(4αR,5S)-1-(4-Fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-1-pyridin-3-yl-N-(2-pyridin-2-ylethyl)methanesulfonamide,N-(cyclopropylmethyl)-2-fluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}benzenesulfonamide,N-allyl-2-fluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}benzenesulfonamide,N-(cyclopropylmethyl)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-2-(trifluoromethyl)benzenesulfonamide,2-chloro-N-(cyclopropylmethyl)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-5-(trifluoromethyl)benzenesulfonamide,N-{4-[((cyclopropylmethyl){[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}amino)sulfonyl]phenyl}acetamide,(5-chloro-N-(cyclopropylmethyl)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-1,3-dimethyl-1H-pyrazole-4-sulfonamide,N-(cyclopropylmethyl)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-7-sulfonamide,N-(cyclopropylmethyl)-N-{[(4αR,5S-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-4-pentylbenzenesulfonamide,N-(cyclopropylmethyl)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}biphenyl-4-sulfonamide,N-(cyolopropylmethyl)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-3,5-dimethylisoxazole-4-sulfonamide,2-chloro-N-(cyclopropylmethyl)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}benzenesulfonamide,(E)-N-(cyclopropylmethyl)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-2-phenylethylenesulfonamide,2-chloro-N-(cyclopropylmethyl)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-4-{[(methylamino)carbonyl]amino}benzenesulfonamide,3-chloro-N-(cyclopropylmethyl)-4-fluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}benzenesulfonamide,N-(2-cyanoethyl)-2-fluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}benzenesulfonamide,2-fluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-hydroxyethyl)benzenesulfonamide, methyl2-[((cyolopropylmethyl){[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}amino)sulfonyl]benzoate,3-chloro-4-fluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-hydroxyethyl)benzenesulfonamide,3-chloro-N-(cyanomethyl)-4-fluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4a,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}benzenesulfonamide,N-(cyolopropylmethyl)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-1-phenylmethanesulfonamide,2-chloro-N-(cyclopropylmethyl)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}benzenesulfonamide,N-(cyanomethyl)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-5-methylisoxazole-4-sulfonamide,4,5-dichloro-N-(cyanomethyl)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}thiophene-2-sulfonamide,N-(cyanomethyl)-3,4-difluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-,1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}benzenesulfonamide,2,3-dichloro-N-(cyanomethyl)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}benzenesulfonamide,4-chloro-N-(cyanomethyl)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-,1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-3-(trifluoromethyl)benzenesulfonamide,4-cyano-N-(cyanomethyl)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}benzenesulfonamide,4-chloro-N-(cyanomethyl)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-2,5-dimethylbenzenesulfonamide,N-(cyanomethyl)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-1-[3-(trifluoromethyl)phenyl]methanesulfonamide,N-(cyanomethyl)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-5-methylthiophene-2-sulfonamide,N-(cyanomethyl)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-sulfonamide,(4αR,5S)-5-({(cyanomethyl)[(2,5-dimethyl-3-furyl)sulfonyl]amino}methyl)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-2-ium,methyl3-[((cyanomethyl){[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}amino)sulfonyl]thiophene-2-carboxylate,(N-(cyanomethyl)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-5-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]thiophene-2-sulfonamide,3-cyano-N-(cyanomethyl)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}benzenesulfonamide,N-(cyanomethyl)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-1-methyl-1H-imidazole-4-sulfonamide,4-(3-chloro-2-cyanophenoxy)-N-(cyanomethyl)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}benzenesulfonamide,N-(cyanomethyl)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-7-sulfonamide,N-(cyanomethyl)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}naphthalene-1-sulfonamide,N-(cyanomethyl)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-2,5-bis(2,2,2-trifluoroethoxy)benzenesulfonamide,N-(cyanomethyl)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}biphenyl-4-sulfonamide,N-(cyanomethyl)-2-fluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}benzenesulfonamide,N-(cyanomethyl)-3,5-difluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}benzenesulfonamide,N-(cyanomethyl)N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-4-(pyridin-2-yloxy)benzenesulfonamide,N-(cyanomethyl)-4-fluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}benzenesulfonamide,N-(cyanomethyl)-2,4,5-trifluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}benzenesulfonamide,N-(cyanomethyl)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methly}-1-phenylmethanesulfonamide,N-(cyanomethyl)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}2-methylbenzenesulfonamide,2-chloro-N-(cyanomethyl)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}benzenesulfonamide,N-(cyanomethyl)-2,4-difluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}benzenesulfonamide,5-chloro-N-(cyanomethyl)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-1,3-dimethyl-1H-pyrazole-4-sulfonamide,N-(cyanomethyl)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}biphenyl-2-sulfonamide,N-(cyanomethyl)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-2-(trifluoromethyl)benzenesulfonamide,2-cyano-N-(cyanomethyl)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}benzenesulfonamide,N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-hydroxyethyl)-5-methylisoxazole-4-sulfonamide,N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-hydroxyethyl)-5-(1,3-oxazol-5-yl)thiophene-2-sulfonamide,3,4-diflouro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-hydroxyethyl)benzenesulfonamide,2-chloro-4-cyano-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-hydroxyethyl)benzenesulfonamide,2,3-dichloro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-hydroxyethyl)benzenesulfonamide,4-cyano-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-hydroxyethyl)benzenesulfonamide,N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-hydroxyethyl)-1-[3-(trifluoromethyl)phenyl]methanesulfonamide,N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-hydroxyethyl)-5-methylthiophene-2-sulfonamide,N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-hydroxyethyl)-1-methyl-3-(trifluoromethyl-1H-pyrazole-4-sulfonamide,N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-hydroxyethyl)-2,5-dimethylfuran-3-sulfonamide,N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-hydroxyethyl)-5-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]thiophene-2-sulfonamide,3-cyano-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-hydroxyethyl)benzenesulfonamide,4-(3-chloro-2-cyanophenoxy)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-hydroxyethyl)benzenesulfonamide,N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-hydroxyethyl)-2-(trifluoromethyl)benzenesulfonamide,N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-hydroxyethyl)-3,5-dimethylisoxazole-4-sulfonamide,3,5-difluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-hydroxyethyl)benzenesulfonamide,methyl2-{[{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}(2-hydroxyethyl)amino]sulfonyl}benzoate,N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-hydroxyethyl)-4-(pyridin-2-yloxy)benzenesulfonamide,N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-hydroxyethyl)-1-phenylmethanesulfonamide,2-chloro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-,4,4,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-hydroxyethyl)-4-{[(methylamino)carbonyl]amino}benzenesulfonamide,N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-hydroxyethyl)-2-methylbenzenesulfonamide,2-cyano-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-hydroxyethyl)benzenesulfonamide,N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-hydroxyethyl)-4-phenoxybenzenesulfonamide,2-chloro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-hydroxyethyl)-5-(trifluoromethyl)benzenesulfonamide,2-chloro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-hydroxyethyl)benzenesulfonamide,2,4-difluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-hydroxyethyl)benzenesulfonamide,5-chloro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-hydroxyethyl)-1,3-dimethyl-1H-pyrazole-4-sulfonamide,N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-hydroxyethyl)biphenyl-2-sulfonamide,N-(4-{[{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}(2-hydroxyethyl)amino]sulfonyl}phenyl)acetamide,2-fluoro-N-[2-(2-fluorophenyl)ethyl]-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}benzenesulfonamide,N-[2-(2-fluorophenyl)ethyl]-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}propane-1-sulfonamide,N-[2-(2-fluorophenyl)ethyl]-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-1-[3-(trifluoromethyl)phenyl]methanesulfonamide,2,2,2-trifluoro-N-[2-(2-fluorophenyl)ethyl]-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}ethanesulfonamide,2-fluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-[2-(2-methoxyphenyl)ethyl]benzenesulfonamide,2-fluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-[2-(4-methylphenyl)ethyl]benzenesulfonamide,N-[2-(2-chlorophenyl)ethyl]-2-fluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}benzenesulfonamide,2,2,2-trifluoro-N-[2-(2-fluorophenyl)ethyl]-N-{[(4αR)-1-(4-fluorophenyl)-4α-methyl-l,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}ethanesulfonamide,2-fluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-methoxyethyl)benzenesulfonamide,N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-methoxyethyl)propane-1-sulfonamide,N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-methoxyethyl)methanesulfonamide,2,2,2-trifluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-methoxyethyl)ethanesulfonamide,N-[2-(2-fluorophenyl)ethyl]-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-sulfonamide,N-[2-(2-fluorophenyl)ethyl]-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-2-(trifluoromethyl)benzenesulfonamide,2-chloro-N-[2-(2-fluorophenyl)ethyl]-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}benzenesulfonamide,N-[2-(2-fluorophenyl)ethyl]-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}cyclopropanesulfonamide,N-[2-(2-fluorophenyl)ethyl]-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}butane-1-sulfonamide,N-[2-(2-fluorophenyl)ethyl]-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-2-methylpropane-1-sulfonamide,N-[2-(2-fluorophenyl)ethyl]-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}octane-1-sulfonamide,1-(2,4-dichlorophenyl)-N-[2-(2-fluorophenyl)ethyl]-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}methanesulfonamide,1-(3-chlorophenyl)-N-[2-(2-fluorophenyl)ethyl]-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}methanesulfonamide,1-(2-chlorophenyl)-N-[2-(2-fluorophenyl)ethyl]-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}methanesulfonamide,N-[2-(2-fluorophenyl)ethyl]-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-1-[2-(trifluoromethyl)phenyl]methanesulfonamide,N-(cyclopropylmethyl)-2,2,2-trifluoro-N-{1-[(4αR)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]ethyl}ethanesulfonamide,N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(tetrahydrofuran-2-ylmethyl)-1-[3-(trifluoromethyl)phenyl]methanesulfonamide,1-(3,4-dichlorophenyl)-N-[2-(2-fluorophenyl)ethyl]-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}methanesulfonamide,3-chloro-4-fluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-[(2S)-2-hydroxypropyl]benzenesulfonamide,2,2,2-trifluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-[(2S)-2-hydroxypropyl]ethanesulfonamide,(1S)-2-{{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}[(2,2,2-trifluoroethyl)sulfonyl]amino}-1-methylethyl2,2,2-trifluoroethanesulfonate,3-chloro-4-fluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-[(2R)-2-hydroxypropyl]benzenesulfonamide,2-fluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-[2-(2-hydroxyphenyl)ethyl]benzenesulfonamde,2-{[{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}(2-hydroxyethyl)amino]sulfonyl}benzamide,2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-methoxyethyl)ethanesulfonamide,N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-[2-(2-methoxyphenyl)ethyl]-1-[3-(trifluoromethyl)phenyl]methanesulfonamide,2,2,2-trifluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-[2-(2-methoxyhenyl)ethyl]ethanesulfonamide,2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-N-[2-(2-fluorophenyl)ethyl]-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}ethanesulfonamide,N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-[2-(2-hydroxyphenyl)ethyl]-1-[3-(trifluoromethyl)phenyl]methanesulfonamide,N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-[2-(2-hydroxyphenyl)ethyl]-3,5-dimethylisoxazole-4-sulfonamide,N-[2-(2-fluorophenyl)ethyl]-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-1-pyridin-3-ylmethanesulfonamide,N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-[2-(2-methoxyphenyl)ethyl]-1-pyridin-3-ylmethanesulfonamide,2,2,2-trifluoro-N-{[(4αR,5S)-1-4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-[2-(3-methoxyphenyl)ethyl]ethanesulfonamide,2,2,2-trifluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-[2-(4-methoxyphenyl)ethyl]ethanesulfonamide,2,2,2-trifluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-pyridin-2-ylethyl)ethanesulfonamide,2,2,2-trifluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-pyridin-4-ylethyl)ethanesulfonamide,2,2,2-trifluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-[2-(4-hydroxyphenyl)ethyl]ethanesulfonamide,N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-[2-(2-hydroxyphenyl)ethyl]-1-pyridin-3-ylmethanesulfonamide,2,2,2-trifluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(pyridazin-3-ylmethyl)ethanesulfonamide,N-(3,3-difluoro-2-hydroxypropyl)-2,2,2-trifluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}ethanesulfonamide,2,2-difluoro-1-({{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}[(2,2,2-trifluoroethyl)sulfonyl]amino}methyl)ethyl2,2,2-trifluoroethanesulfonate,2,2,2-trifluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-[(1-hydroxycyclopropyl)methyl]ethanesulfonamide,1-({{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}[(2,2,2-trifluoroethyl)sulfonyl]amino}methyl)cyclopropyl2,2,2-trifluoroethanesulfonate,2,2,2-trifluoro-N-[2-(2-fluorophenyl)ethyl]-N-{[(4αR,5S)-4α-methyl-1-phenyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}ethanesulfonamide,2,2,2-trifluoro-N-{[(4αR,5S)-4α-methyl-1-phenyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-pyridin-2-ylethyl)ethanesulfonamide,2,2,2-trifluoro-N-[2-(2-methoxyphenyl)ethyl]-N-{[(4αR,5S)-4α-methyl-1phenyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}ethanesulfonamide,N-{[(4αR,5S)-4α-methyl-1-phenyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-1-pyridin-3-yl-N-(2-pyridin-2-ylethyl)methanesulfonamide,N-[2-(2-hydroxyphenyl)ethyl]-N-{[(4αR,5S)-4α-methyl-1-phenyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-1-pyridin-3-ylmethanesulfonamide,2,2,2-trifluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-hydroxy-2-pyridin-2-ylethyl)ethanesulfonamide,2,2,2-trifluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-hydroxy-2-pyridin-3-ylethyl)ethanesulfonamide,2,2,2-trifluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-hydroxy-2-pyridin-4-ylethyl)ethanesulfonamide,2-{{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}[(2,2,2-trifluoroethyl)sulfonyl]amino}-1-pyridin-2-ylethyl2,2,2-trifluoroethanesulfonate,2,2,2-trifluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-pyridin-3-ylpropyl)ethanesulfonamide,N-(3-amino-4,4,4-trifluorobutyl)-2,2,2-trifluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}ethanesulfonamide,N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(3,3,3-trifluoro-2-hydroxypropyl)propane-1-sulfonamide,N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-1-pyridin-3-yl-N-(3,3,3-trifluoro-2-hydroxypropyl)methanesulfonamide,N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-1-methyl-N-(2-pyridin-2-ylethyl)-3-(trifluoromethyl)-1H-pyrazole-4-sulfonamide,N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-pyridin-2-ylethyl)propane-1-sulfonamide,2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-pyridin-2-ylethyl)ethanesulfonamide,N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-pyridin-2-ylethyl)-1-[2-(trifluoromethyl)phenyl]methanesulfonamide,N-(3,3-difluoro-2-hydroxypropyl)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-1-pyridin-3-ylmethanesulfonamide,N-(3,3-difluoro-2-hydroxypropyl)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}propane-1-sulfonamide,N-(3,3-difluoro-2-hydroxypropyl)-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-sulfonaimde,N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-hydroxy-2-pyridin-2-ylethyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-sulfonamide,2-fluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-oxoethyl)benzenesulfonamide,methyl2-(2-{{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1-,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}[(2,2,2-trifluoroethyl)sulfonyl]amino}ethyl)benzoate,methyl5-chloro-2-(2-{{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}[(2,2,2-trifluoroethyl)sulfonyl]amino}ethyl)benzoate,N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-3,5-dimethylisoxazole-4-sulfonamide,methyl2-{[{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}(3,3,3-trifluoro-2-hydroxypropyl)amino]sulfonyl}methyl)benzoate,2,2,2-trifluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-{2-[2-(hydroxymethyl)phenyl]ethyl}ethanesulfonamide,2-({[{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}(3,3,3-trifluoro-2-hydroxypropyl)amino]sulfonyl}methyl)benzoicacid, N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-1-pyridin-2-yl-N-(2-pyridin-2-ylethyl)methanesulfonaimde,N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methly}-1-pyridin-4-yl-N-(2-pyridin-2-ylethyl)methanesulfonamide,2-({[{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,4,5,6,7-hexahydrocyclopenta[f]1indazol-5-yl]methyl}(3,3,3-trifluoro-2-hydroxypropyl)amino]sulfonyl}methyl)benzamide,N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-[(2R)-2-hydroxypropyl]-3,5-dimethylisoxazole-4-sulfonamide,N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-1-pyridin-3-ylmethanesulfonamide,N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-3,5-dimethyl-N-(tetrahydrofuran-2-ylmethyl)isoxazole-4-sulfoanmide,N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-methoxyethyl)ethanesulfonamide,N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-methoxyethyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-sulfonamide,N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-methoxyethyl)-3,5-dimethylisoxazole-4-sulfonamide,N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(tetrahydrofuran-2-ylmethyl)ethanesulfonamide,N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-1-methyl-N-(tetrahydrofuran-2-ylmethyl)-3-(trifluoromethyl)-1H-pyrazole-4-sulfonamide,N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N,3,5-trimethylisoxazole-4-sulfonamide,2,2,2-trifluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-methylethanesulfonamide,N-ethyl-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-3,5-dimethylisoxazole-4-sulfonamide,N-ethyl-2,2,2-trifluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}ethansulfonamide,methyl2-[({{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl,1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}[(2R)-2-hydroxypropyl]amino}sulfonyl)methyl]benzoate,methyl2-[({{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl,1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}[(2S)-2-hydroxypropyl]amino}sulfonyl)methyl]benzoate,methyl2-({[{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}(3,3,3-trifluoro-2-hydroxypropyl)amino]sulfonyl}methyl)benzoate,2,2,2-trifluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-{2-[2-(hydroxymethyl)phenyl]ethyl}ethanesulfonamide,2-[({{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}[(2R)-2-hydroxypropyl]amino}sulfonyl)methyl]benzoicacid,2-[({{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}[(2R)-2-hydroxypropyl]amino}sulfonyl)methyl]benzoicacid,2-[({{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}[(2R)-2-hydroxypropyl]amino}sulfonyl)methyl]benzamide,2-[({{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}[(2R)-2-hydroxypropyl]amino}sulfonyl)methyl]benzamide,methyl2-({{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}[(2R)-2-hydroxypropyl]amino}sulfonyl)benzoate,methyl2-({{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}[(2R)-2-hydroxypropyl]amino}sulfonyl)benzoate,methyl2-{[([(2-(2-fluorophenyl)ethyl]{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}amino)sulfonyl]methyl}benzoate,methyl2-[([2-(2-fluorophenyl)ethyl]{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}amino)sulfonyl]benzoate,2-{[([2-(2-fluorophenyl)ethyl]{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}amino)sulfonyl]methyl}benzamide,4-{[{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}(tetrahydrofuran-2-ylmethyl)amino]sulfonyl}benzamide,3-[((2-fluorobenzyl){[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}amino)sulfonyl]benzamide,2,2,2-trifluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(3-phenylpropyl)ethanesulfonamide,N-{[(4αR,55)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-3,5-dimethyl-N-(3-phenylpropyl)isoxazole-4-sulfonamide,2-fluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(3-phenylpropyl)benzenesulfonamide,2-({[{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}(2-pyridin-2-ylethyl)amino]sulfonyl}methyl)benzamide,N-{1-[(4αR)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]ethyl}-1-pyridin-3-yl-N-(2-pyridin-2-ylethyl)methanesulfonamide,2-({[{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}(2-hydroxyethyl)amino]sulfonyl}methyl)benzamide,2-fluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-(2-hydroxy-2-methylpropyl)benzenesulfonamide,and2-fluoro-N-{[(4αR,5S)-1-(4-fluorophenyl)-4α-methyl-1,4,4α,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]methyl}-N-[(1-hydroxycyclopropyl)methyl]benzenesulfonamide,or a pharmaceutically acceptable salt thereof.
 14. A pharmaceuticalcomposition comprising a compound according to claim 1 in combinationwith a pharmaceutically acceptable carrier.